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1. Detection and genomic analysis of BRAF fusions in Juvenile Pilocytic Astrocytoma through the combination and integration of multi-omic data.

Author

Zwaig, M, Baguette, A, Hu, B, Johnston, M, Lakkis, H, Nakada, EM, Faury, D, Juretic, N, Ellezam, B, Weil, AG, Karamchandani, J, Majewski, J, Blanchette, M, Taylor, MD, Gallo, M, Kleinman, CL, Jabado, N, Ragoussis, J, Zwaig, M, Baguette, A, Hu, B, Johnston, M, Lakkis, H, Nakada, EM, Faury, D, Juretic, N, Ellezam, B, Weil, AG, Karamchandani, J, Majewski, J, Blanchette, M, Taylor, MD, Gallo, M, Kleinman, CL, Jabado, N, and Ragoussis, J

Abstract

BACKGROUND: Juvenile Pilocytic Astrocytomas (JPAs) are one of the most common pediatric brain tumors, and they are driven by aberrant activation of the mitogen-activated protein kinase (MAPK) signaling pathway. RAF-fusions are the most common genetic alterations identified in JPAs, with the prototypical KIAA1549-BRAF fusion leading to loss of BRAF's auto-inhibitory domain and subsequent constitutive kinase activation. JPAs are highly vascular and show pervasive immune infiltration, which can lead to low tumor cell purity in clinical samples. This can result in gene fusions that are difficult to detect with conventional omics approaches including RNA-Seq. METHODS: To this effect, we applied RNA-Seq as well as linked-read whole-genome sequencing and in situ Hi-C as new approaches to detect and characterize low-frequency gene fusions at the genomic, transcriptomic and spatial level. RESULTS: Integration of these datasets allowed the identification and detailed characterization of two novel BRAF fusion partners, PTPRZ1 and TOP2B, in addition to the canonical fusion with partner KIAA1549. Additionally, our Hi-C datasets enabled investigations of 3D genome architecture in JPAs which showed a high level of correlation in 3D compartment annotations between JPAs compared to other pediatric tumors, and high similarity to normal adult astrocytes. We detected interactions between BRAF and its fusion partners exclusively in tumor samples containing BRAF fusions. CONCLUSIONS: We demonstrate the power of integrating multi-omic datasets to identify low frequency fusions and characterize the JPA genome at high resolution. We suggest that linked-reads and Hi-C could be used in clinic for the detection and characterization of JPAs.

Published
2022

3. Non-random aneuploidy specifies subgroups of pilocytic astrocytoma and correlates with older age

Author

Fontebasso, AM, Shirinian, M, Khuong-Quang, D-A, Bechet, D, Gayden, T, Kool, M, De Jay, N, Jacob, K, Gerges, N, Hutter, B, Seker-Cin, H, Witt, H, Montpetit, A, Brunet, S, Lepage, P, Bourret, G, Klekner, A, Bognar, L, Hauser, P, Garami, M, Farmer, J-P, Montes, J-L, Atkinson, J, Lambert, S, Kwan, T, Korshunov, A, Tabori, U, Collins, VP, Albrecht, S, Faury, D, Pfister, SM, Paulus, W, Hasselblatt, M, Jones, DTW, Jabado, N, Fontebasso, AM, Shirinian, M, Khuong-Quang, D-A, Bechet, D, Gayden, T, Kool, M, De Jay, N, Jacob, K, Gerges, N, Hutter, B, Seker-Cin, H, Witt, H, Montpetit, A, Brunet, S, Lepage, P, Bourret, G, Klekner, A, Bognar, L, Hauser, P, Garami, M, Farmer, J-P, Montes, J-L, Atkinson, J, Lambert, S, Kwan, T, Korshunov, A, Tabori, U, Collins, VP, Albrecht, S, Faury, D, Pfister, SM, Paulus, W, Hasselblatt, M, Jones, DTW, and Jabado, N

Abstract

Pilocytic astrocytoma (PA) is the most common brain tumor in children but is rare in adults, and hence poorly studied in this age group. We investigated 222 PA and report increased aneuploidy in older patients. Aneuploid genomes were identified in 45% of adult compared with 17% of pediatric PA. Gains were non-random, favoring chromosomes 5, 7, 6 and 11 in order of frequency, and preferentially affecting non-cerebellar PA and tumors with BRAF V600E mutations and not with KIAA1549-BRAF fusions or FGFR1 mutations. Aneuploid PA differentially expressed genes involved in CNS development, the unfolded protein response, and regulators of genomic stability and the cell cycle (MDM2, PLK2),whose correlated programs were overexpressed specifically in aneuploid PA compared to other glial tumors. Thus, convergence of pathways affecting the cell cycle and genomic stability may favor aneuploidy in PA, possibly representing an additional molecular driver in older patients with this brain tumor.

Published
2015

4. HIGH GRADE GLIOMAS AND DIPG

Author

Classen, C. F., primary, William, D., additional, Linnebacher, M., additional, Farhod, A., additional, Kedr, W., additional, Elsabe, B., additional, Fadel, S., additional, Van Gool, S., additional, De Vleeschouwer, S., additional, Koks, C., additional, Garg, A., additional, Ehrhardt, M., additional, Riva, M., additional, Agostinis, P., additional, Graf, N., additional, Yao, T.-W., additional, Yoshida, Y., additional, Zhang, J., additional, Ozawa, T., additional, James, D., additional, Nicolaides, T., additional, Kebudi, R., additional, Cakir, F. B., additional, Gorgun, O., additional, Agaoglu, F. Y., additional, Darendeliler, E., additional, Al-Kofide, A., additional, Al-Shail, E., additional, Khafaga, Y., additional, Al-Hindi, H., additional, Dababo, M., additional, Haq, A. U., additional, Anas, M., additional, Barria, M. G., additional, Siddiqui, K., additional, Hassounah, M., additional, Ayas, M., additional, van Zanten, S. V., additional, Jansen, M., additional, van Vuurden, D., additional, Huisman, M., additional, Vugts, D., additional, Hoekstra, O., additional, van Dongen, G., additional, Kaspers, G., additional, Cockle, J., additional, Ilett, E., additional, Scott, K., additional, Bruning-Richardson, A., additional, Picton, S., additional, Short, S., additional, Melcher, A., additional, Benesch, M., additional, Warmuth-Metz, M., additional, von Bueren, A. O., additional, Hoffmann, M., additional, Pietsch, T., additional, Kortmann, R.-D., additional, Eyrich, M., additional, Rutkowski, S., additional, Fruhwald, M. C., additional, Faber, J., additional, Kramm, C., additional, Porkholm, M., additional, Valanne, L., additional, Lonnqvist, T., additional, Holm, S., additional, Lannering, B., additional, Riikonen, P., additional, Wojcik, D., additional, Sehested, A., additional, Clausen, N., additional, Harila-Saari, A., additional, Schomerus, E., additional, Thorarinsdottir, H. K., additional, Lahteenmaki, P., additional, Arola, M., additional, Thomassen, H., additional, Saarinen-Pihkala, U. M., additional, Kivivuori, S.-M., additional, Buczkowicz, P., additional, Hoeman, C., additional, Rakopoulos, P., additional, Pajovic, S., additional, Morrison, A., additional, Bouffet, E., additional, Bartels, U., additional, Becher, O., additional, Hawkins, C., additional, Gould, T. W. A., additional, Rahman, C. V., additional, Smith, S. J., additional, Barrett, D. A., additional, Shakesheff, K. M., additional, Grundy, R. G., additional, Rahman, R., additional, Barua, N., additional, Cronin, D., additional, Gill, S., additional, Lowisl, S., additional, Hochart, A., additional, Maurage, C.-A., additional, Rocourt, N., additional, Vinchon, M., additional, Kerdraon, O., additional, Escande, F., additional, Grill, J., additional, Pick, V. K., additional, Leblond, P., additional, Burzynski, G., additional, Janicki, T., additional, Burzynski, S., additional, Marszalek, A., additional, Ramani, N., additional, Zaky, W., additional, Kannan, G., additional, Morani, A., additional, Sandberg, D., additional, Ketonen, L., additional, Maher, O., additional, Corrales-Medina, F., additional, Meador, H., additional, Khatua, S., additional, Brassesco, M., additional, Delsin, L., additional, Roberto, G., additional, Silva, C., additional, Ana, L., additional, Rego, E., additional, Scrideli, C., additional, Umezawa, K., additional, Tone, L., additional, Kim, S. J., additional, Kim, C.-Y., additional, Kim, I.-A., additional, Han, J. H., additional, Choi, B.-S., additional, Ahn, H. S., additional, Choi, H. S., additional, Haque, F., additional, Layfield, R., additional, Grundy, R., additional, Gandola, L., additional, Pecori, E., additional, Biassoni, V., additional, Schiavello, E., additional, Chiruzzi, C., additional, Spreafico, F., additional, Modena, P., additional, Bach, F., additional, Pignoli, E., additional, Massimino, M., additional, Drogosiewicz, M., additional, Dembowska-Baginska, B., additional, Jurkiewicz, E., additional, Filipek, I., additional, Perek-Polnik, M., additional, Swieszkowska, E., additional, Perek, D., additional, Bender, S., additional, Jones, D. T., additional, Warnatz, H.-J., additional, Hutter, B., additional, Zichner, T., additional, Gronych, J., additional, Korshunov, A., additional, Eils, R., additional, Korbel, J. O., additional, Yaspo, M.-L., additional, Lichter, P., additional, Pfister, S. M., additional, Yadavilli, S., additional, Becher, O. J., additional, Kambhampati, M., additional, Packer, R. J., additional, Nazarian, J., additional, Lechon, F. C., additional, Fowkes, L., additional, Khabra, K., additional, Martin-Retortillo, L. M., additional, Marshall, L. V., additional, Vaidya, S., additional, Koh, D.-M., additional, Leach, M. O., additional, Pearson, A. D., additional, Zacharoulis, S., additional, Schrey, D., additional, Barone, G., additional, Panditharatna, E., additional, Stampar, M., additional, Siu, A., additional, Gordish-Dressman, H., additional, Devaney, J., additional, Hwang, E. I., additional, Chung, A. H., additional, Mittapalli, R. K., additional, Elmquist, W. F., additional, Castel, D., additional, Debily, M.-A., additional, Philippe, C., additional, Truffaux, N., additional, Taylor, K., additional, Calmon, R., additional, Boddaert, N., additional, Le Dret, L., additional, Saulnier, P., additional, Lacroix, L., additional, Mackay, A., additional, Jones, C., additional, Puget, S., additional, Sainte-Rose, C., additional, Blauwblomme, T., additional, Varlet, P., additional, Entz-Werle, N., additional, Maugard, C., additional, Bougeard, G., additional, Nguyen, A., additional, Chenard, M. P., additional, Schneider, A., additional, Gaub, M. P., additional, Tsoli, M., additional, Vanniasinghe, A., additional, Luk, P., additional, Dilda, P., additional, Haber, M., additional, Hogg, P., additional, Ziegler, D., additional, Simon, S., additional, Monje, M., additional, Gurova, K., additional, Gudkov, A., additional, Zapotocky, M., additional, Churackova, M., additional, Malinova, B., additional, Zamecnik, J., additional, Kyncl, M., additional, Tichy, M., additional, Puchmajerova, A., additional, Stary, J., additional, Sumerauer, D., additional, Boult, J., additional, Vinci, M., additional, Perryman, L., additional, Box, G., additional, Jury, A., additional, Popov, S., additional, Ingram, W., additional, Eccles, S., additional, Robinson, S., additional, Emir, S., additional, Demir, H. A., additional, Bayram, C., additional, Cetindag, F., additional, Kabacam, G. B., additional, Fettah, A., additional, Li, J., additional, Jamin, Y., additional, Cummings, C., additional, Bamber, J., additional, Sinkus, R., additional, Nandhabalan, M., additional, Bjerke, L., additional, Burford, A., additional, von Bueren, A., additional, Baudis, M., additional, Clarke, P., additional, Collins, I., additional, Workman, P., additional, Olaciregui, N., additional, Mora, J., additional, Carcaboso, A., additional, Bullock, A., additional, Alonso, M., additional, de Torres, C., additional, Cruz, O., additional, Pencreach, E., additional, Moussalieh, F. M., additional, Guenot, D., additional, Namer, I., additional, Pollack, I., additional, Jakacki, R., additional, Butterfield, L., additional, Hamilton, R., additional, Panigrahy, A., additional, Potter, D., additional, Connelly, A., additional, Dibridge, S., additional, Whiteside, T., additional, Okada, H., additional, Ahsan, S., additional, Raabe, E., additional, Haffner, M., additional, Warren, K., additional, Quezado, M., additional, Ballester, L., additional, Eberhart, C., additional, Rodriguez, F., additional, Ramachandran, C., additional, Nair, S., additional, Quirrin, K.-W., additional, Khatib, Z., additional, Escalon, E., additional, Melnick, S., additional, Classen, C. F., additional, Hofmann, M., additional, Schmid, I., additional, Simon, T., additional, Maass, E., additional, Russo, A., additional, Fleischhack, G., additional, Becker, M., additional, Hauch, H., additional, Sander, A., additional, Grasso, C., additional, Berlow, N., additional, Liu, L., additional, Davis, L., additional, Huang, E., additional, Woo, P., additional, Tang, Y., additional, Ponnuswami, A., additional, Chen, S., additional, Huang, Y., additional, Hutt-Cabezas, M., additional, Dret, L., additional, Meltzer, P., additional, Mao, H., additional, Abraham, J., additional, Fouladi, M., additional, Svalina, M. N., additional, Wang, N., additional, Hulleman, E., additional, Li, X.-N., additional, Keller, C., additional, Spellman, P. T., additional, Pal, R., additional, Jansen, M. H. A., additional, Sewing, A. C. P., additional, Lagerweij, T., additional, Vuchts, D. J., additional, van Vuurden, D. G., additional, Caretti, V., additional, Wesseling, P., additional, Kaspers, G. J. L., additional, Cohen, K., additional, Pearl, M., additional, Kogiso, M., additional, Zhang, L., additional, Qi, L., additional, Lindsay, H., additional, Lin, F., additional, Berg, S., additional, Muscal, J., additional, Amayiri, N., additional, Tabori, U., additional, Campbel, B., additional, Bakry, D., additional, Aronson, M., additional, Durno, C., additional, Gallinger, S., additional, Malkin, D., additional, Qaddumi, I., additional, Musharbash, A., additional, Swaidan, M., additional, Al-Hussaini, M., additional, Shandilya, S., additional, McCully, C., additional, Murphy, R., additional, Akshintala, S., additional, Cole, D., additional, Macallister, R. P., additional, Cruz, R., additional, Widemann, B., additional, Salloum, R., additional, Smith, A., additional, Glaunert, M., additional, Ramkissoon, A., additional, Peterson, S., additional, Baker, S., additional, Chow, L., additional, Sandgren, J., additional, Pfeifer, S., additional, Popova, S., additional, Alafuzoff, I., additional, de Stahl, T. D., additional, Pietschmann, S., additional, Kerber, M. J., additional, Zwiener, I., additional, Henke, G., additional, Muller, K., additional, Sieow, N. Y.-F., additional, Hoe, R. H. M., additional, Tan, A. M., additional, Chan, M. Y., additional, Soh, S. Y., additional, Burrell, K., additional, Chornenkyy, Y., additional, Remke, M., additional, Golbourn, B., additional, Barzczyk, M., additional, Taylor, M., additional, Rutka, J., additional, Dirks, P., additional, Zadeh, G., additional, Agnihotri, S., additional, Hashizume, R., additional, Ihara, Y., additional, Andor, N., additional, Chen, X., additional, Lerner, R., additional, Huang, X., additional, Tom, M., additional, Solomon, D., additional, Mueller, S., additional, Petritsch, C., additional, Zhang, Z., additional, Gupta, N., additional, Waldman, T., additional, Dujua, A., additional, Co, J., additional, Hernandez, F., additional, Doromal, D., additional, Hegde, M., additional, Wakefield, A., additional, Brawley, V., additional, Grada, Z., additional, Byrd, T., additional, Chow, K., additional, Krebs, S., additional, Heslop, H., additional, Gottschalk, S., additional, Yvon, E., additional, Ahmed, N., additional, Cornilleau, G., additional, Paulsson, J., additional, Andreiuolo, F., additional, Guerrini-Rousseau, L., additional, Geoerger, B., additional, Vassal, G., additional, Ostman, A., additional, Parsons, D. W., additional, Trevino, L. R., additional, Gao, F., additional, Shen, X., additional, Hampton, O., additional, Kosigo, M., additional, Baxter, P. A., additional, Su, J. M., additional, Chintagumpala, M., additional, Dauser, R., additional, Adesina, A., additional, Plon, S. E., additional, Wheeler, D. A., additional, Lau, C. C., additional, Gielen, G., additional, Muehlen, A. z., additional, Kwiecien, R., additional, Wolff, J., additional, Lulla, R. R., additional, Laskowski, J., additional, Goldman, S., additional, Gopalakrishnan, V., additional, Fangusaro, J., additional, Kieran, M., additional, Fontebasso, A., additional, Papillon-Cavanagh, S., additional, Schwartzentruber, J., additional, Nikbakht, H., additional, Gerges, N., additional, Fiset, P.-O., additional, Bechet, D., additional, Faury, D., additional, De Jay, N., additional, Ramkissoon, L., additional, Corcoran, A., additional, Jones, D., additional, Sturm, D., additional, Johann, P., additional, Tomita, T., additional, Nagib, M., additional, Bendel, A., additional, Goumnerova, L., additional, Bowers, D. C., additional, Leonard, J. R., additional, Rubin, J. B., additional, Alden, T., additional, DiPatri, A., additional, Browd, S., additional, Leary, S., additional, Jallo, G., additional, Prados, M. D., additional, Banerjee, A., additional, Carret, A.-S., additional, Ellezam, B., additional, Crevier, L., additional, Klekner, A., additional, Bognar, L., additional, Hauser, P., additional, Garami, M., additional, Myseros, J., additional, Dong, Z., additional, Siegel, P. M., additional, Gump, W., additional, Ayyanar, K., additional, Ragheb, J., additional, Krieger, M., additional, Kiehna, E., additional, Robison, N., additional, Harter, D., additional, Gardner, S., additional, Handler, M., additional, Foreman, N., additional, Brahma, B., additional, MacDonald, T., additional, Malkin, H., additional, Chi, S., additional, Manley, P., additional, Bandopadhayay, P., additional, Greenspan, L., additional, Ligon, A., additional, Albrecht, S., additional, Ligon, K. L., additional, Majewski, J., additional, Jabado, N., additional, Cordero, F., additional, Halvorson, K., additional, Taylor, I., additional, Hutt, M., additional, Weingart, M., additional, Price, A., additional, Kantar, M., additional, Onen, S., additional, Kamer, S., additional, Turhan, T., additional, Kitis, O., additional, Ertan, Y., additional, Cetingul, N., additional, Anacak, Y., additional, Akalin, T., additional, Ersahin, Y., additional, Mason, G., additional, Ho, C., additional, Crozier, F., additional, Vezina, G., additional, Packer, R., additional, Hwang, E., additional, Gilheeney, S., additional, Millard, N., additional, DeBraganca, K., additional, Khakoo, Y., additional, Kramer, K., additional, Wolden, S., additional, Donzelli, M., additional, Fischer, C., additional, Petriccione, M., additional, Dunkel, I., additional, Afzal, S., additional, Fleming, A., additional, Larouche, V., additional, Zelcer, S., additional, Johnston, D. L., additional, Kostova, M., additional, Mpofu, C., additional, Decarie, J.-C., additional, Strother, D., additional, Lafay-Cousin, L., additional, Eisenstat, D., additional, Fryer, C., additional, Hukin, J., additional, Hsu, M., additional, Lasky, J., additional, Moore, T., additional, Liau, L., additional, Davidson, T., additional, Prins, R., additional, Hassal, T., additional, Baugh, J., additional, Kirkendall, J., additional, Doughman, R., additional, Leach, J., additional, Jones, B., additional, Miles, L., additional, Hargrave, D., additional, Jacques, T., additional, Savage, S., additional, Saunders, D., additional, Wallace, R., additional, Flutter, B., additional, Morgenestern, D., additional, Blanco, E., additional, Howe, K., additional, Lowdell, M., additional, Samuel, E., additional, Michalski, A., additional, Anderson, J., additional, Arakawa, Y., additional, Umeda, K., additional, Watanabe, K.-i., additional, Mizowaki, T., additional, Hiraoka, M., additional, Hiramatsu, H., additional, Adachi, S., additional, Kunieda, T., additional, Takagi, Y., additional, Miyamoto, S., additional, Venneti, S., additional, Santi, M., additional, Felicella, M. M., additional, Sullivan, L. M., additional, Dolgalev, I., additional, Martinez, D., additional, Perry, A., additional, Lewis, P. W., additional, Allis, D. C., additional, Thompson, C. B., additional, and Judkins, A. R., additional

Published
2014
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5. Mutations in SETD2 and genes affecting histone H3K36 methylation target hemispheric high-grade gliomas

Author

Fontebasso, AM, Schwartzentruber, J, Dong-Anh, K-Q, Liu, X-Y, Sturm, D, Korshunov, A, Jones, DTW, Witt, H, Kool, M, Albrecht, S, Fleming, A, Hadjadj, D, Busche, S, Lepage, P, Montpetit, A, Staffa, A, Gerges, N, Zakrzewska, M, Zakrzewski, K, Liberski, PP, Hauser, P, Garami, M, Klekner, A, Bognar, L, Zadeh, G, Faury, D, Pfister, SM, Jabado, N, Majewski, J, Fontebasso, AM, Schwartzentruber, J, Dong-Anh, K-Q, Liu, X-Y, Sturm, D, Korshunov, A, Jones, DTW, Witt, H, Kool, M, Albrecht, S, Fleming, A, Hadjadj, D, Busche, S, Lepage, P, Montpetit, A, Staffa, A, Gerges, N, Zakrzewska, M, Zakrzewski, K, Liberski, PP, Hauser, P, Garami, M, Klekner, A, Bognar, L, Zadeh, G, Faury, D, Pfister, SM, Jabado, N, and Majewski, J

Abstract

Recurrent mutations affecting the histone H3.3 residues Lys27 or indirectly Lys36 are frequent drivers of pediatric high-grade gliomas (over 30% of HGGs). To identify additional driver mutations in HGGs, we investigated a cohort of 60 pediatric HGGs using whole-exome sequencing (WES) and compared them to 543 exomes from non-cancer control samples. We identified mutations in SETD2, a H3K36 trimethyltransferase, in 15% of pediatric HGGs, a result that was genome-wide significant (FDR = 0.029). Most SETD2 alterations were truncating mutations. Sequencing the gene in this cohort and another validation cohort (123 gliomas from all ages and grades) showed SETD2 mutations to be specific to high-grade tumors affecting 15% of pediatric HGGs (11/73) and 8% of adult HGGs (5/65) while no SETD2 mutations were identified in low-grade diffuse gliomas (0/45). Furthermore, SETD2 mutations were mutually exclusive with H3F3A mutations in HGGs (P = 0.0492) while they partly overlapped with IDH1 mutations (4/14), and SETD2-mutant tumors were found exclusively in the cerebral hemispheres (P = 0.0055). SETD2 is the only H3K36 trimethyltransferase in humans, and SETD2-mutant tumors showed a substantial decrease in H3K36me3 levels (P < 0.001), indicating that the mutations are loss-of-function. These data suggest that loss-of-function SETD2 mutations occur in older children and young adults and are specific to HGG of the cerebral cortex, similar to the H3.3 G34R/V and IDH mutations. Taken together, our results suggest that mutations disrupting the histone code at H3K36, including H3.3 G34R/V, IDH1 and/or SETD2 mutations, are central to the genesis of hemispheric HGGs in older children and young adults.

Published
2013

6. K27M mutation in histone H3.3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas

Author

Dong-Anh, K-Q, Buczkowicz, P, Rakopoulos, P, Liu, X-Y, Fontebasso, AM, Bouffet, E, Bartels, U, Albrecht, S, Schwartzentruber, J, Letourneau, L, Bourgey, M, Bourque, G, Montpetit, A, Bourret, G, Lepage, P, Fleming, A, Lichter, P, Kool, M, von Deimling, A, Sturm, D, Korshunov, A, Faury, D, Jones, DT, Majewski, J, Pfister, SM, Jabado, N, Hawkins, C, Dong-Anh, K-Q, Buczkowicz, P, Rakopoulos, P, Liu, X-Y, Fontebasso, AM, Bouffet, E, Bartels, U, Albrecht, S, Schwartzentruber, J, Letourneau, L, Bourgey, M, Bourque, G, Montpetit, A, Bourret, G, Lepage, P, Fleming, A, Lichter, P, Kool, M, von Deimling, A, Sturm, D, Korshunov, A, Faury, D, Jones, DT, Majewski, J, Pfister, SM, Jabado, N, and Hawkins, C

Abstract

Pediatric glioblastomas (GBM) including diffuse intrinsic pontine gliomas (DIPG) are devastating brain tumors with no effective therapy. Here, we investigated clinical and biological impacts of histone H3.3 mutations. Forty-two DIPGs were tested for H3.3 mutations. Wild-type versus mutated (K27M-H3.3) subgroups were compared for HIST1H3B, IDH, ATRX and TP53 mutations, copy number alterations and clinical outcome. K27M-H3.3 occurred in 71 %, TP53 mutations in 77 % and ATRX mutations in 9 % of DIPGs. ATRX mutations were more frequent in older children (p < 0.0001). No G34V/R-H3.3, IDH1/2 or H3.1 mutations were identified. K27M-H3.3 DIPGs showed specific copy number changes, including all gains/amplifications of PDGFRA and MYC/PVT1 loci. Notably, all long-term survivors were H3.3 wild type and this group of patients had better overall survival. K27M-H3.3 mutation defines clinically and biologically distinct subgroups and is prevalent in DIPG, which will impact future therapeutic trial design. K27M- and G34V-H3.3 have location-based incidence (brainstem/cortex) and potentially play distinct roles in pediatric GBM pathogenesis. K27M-H3.3 is universally associated with short survival in DIPG, while patients wild-type for H3.3 show improved survival. Based on prognostic and therapeutic implications, our findings argue for H3.3-mutation testing at diagnosis, which should be rapidly integrated into the clinical decision-making algorithm, particularly in atypical DIPG.

Published
2012

7. CELL BIOLOGY AND SIGNALING

Author

Agarwal, M., primary, Nitta, R., additional, Dovat, S., additional, Li, G., additional, Arita, H., additional, Narita, Y., additional, Fukushima, S., additional, Tateishi, K., additional, Matsushita, Y., additional, Yoshida, A., additional, Miyakita, Y., additional, Ohno, M., additional, Collins, V. P., additional, Kawahara, N., additional, Shibui, S., additional, Ichimura, K., additional, Kahn, S. A., additional, Gholamin, S., additional, Junier, M.-P., additional, Chneiweiss, H., additional, Weissman, I., additional, Mitra, S., additional, Cheshier, S., additional, Avril, T., additional, Hamlat, A., additional, Le Reste, P.-J., additional, Mosser, J., additional, Quillien, V., additional, Carrato, C., additional, Munoz-Marmol, A., additional, Serrano, L., additional, Pijuan, L., additional, Hostalot, C., additional, Villa, S. l., additional, Ariza, A., additional, Etxaniz, O., additional, Balana, C., additional, Benveniste, E. T., additional, Zheng, Y., additional, McFarland, B., additional, Drygin, D., additional, Bellis, S., additional, Bredel, M., additional, Lotsch, D., additional, Engelmaier, C., additional, Allerstorfer, S., additional, Grusch, M., additional, Pichler, J., additional, Weis, S., additional, Hainfellner, J., additional, Marosi, C., additional, Spiegl-Kreinecker, S., additional, Berger, W., additional, Bronisz, A., additional, Nowicki, M. O., additional, Wang, Y., additional, Ansari, K., additional, Chiocca, E. A., additional, Godlewski, J., additional, Brown, K., additional, Kwatra, M., additional, Bui, T., additional, Zhu, S., additional, Kozono, D., additional, Li, J., additional, Kushwaha, D., additional, Carter, B., additional, Chen, C., additional, Schulte, J., additional, Srikanth, M., additional, Das, S., additional, Zhang, J., additional, Lathia, J., additional, Yin, L., additional, Rich, J., additional, Olson, E., additional, Kessler, J., additional, Chenn, A., additional, Cherry, A., additional, Haas, B., additional, Lin, Y. H., additional, Ong, S.-E., additional, Stella, N., additional, Cifarelli, C. P., additional, Griffin, R. J., additional, Cong, D., additional, Zhu, W., additional, Shi, Y., additional, Clark, P., additional, Kuo, J., additional, Hu, S., additional, Sun, D., additional, Bookland, M., additional, Darbinian, N., additional, Dey, A., additional, Robitaille, M., additional, Remke, M., additional, Faury, D., additional, Maier, C., additional, Malhotra, A., additional, Jabado, N., additional, Taylor, M., additional, Angers, S., additional, Kenney, A., additional, Ren, X., additional, Zhou, H., additional, Schur, M., additional, Baweja, A., additional, Singh, M., additional, Erdreich-Epstein, A., additional, Fu, J., additional, Koul, D., additional, Yao, J., additional, Saito, N., additional, Zheng, S., additional, Verhaak, R., additional, Lu, Z., additional, Yung, W. K. A., additional, Gomez, G., additional, Volinia, S., additional, Croce, C., additional, Brennan, C., additional, Cavenee, W., additional, Furnari, F., additional, Lopez, S. G., additional, Qu, D., additional, Petritsch, C., additional, Gonzalez-Huarriz, M., additional, Aldave, G., additional, Ravi, D., additional, Rubio, A., additional, Diez-Valle, R., additional, Marigil, M., additional, Jauregi, P., additional, Vera, B., additional, Rocha, A. A. d. l., additional, Tejada-Solis, S., additional, Alonso, M. M., additional, Gopal, U., additional, Isaacs, J., additional, Gruber-Olipitz, M., additional, Dabral, S., additional, Ramkissoon, S., additional, Kung, A., additional, Pak, E., additional, Chung, J., additional, Theisen, M., additional, Sun, Y., additional, Monrose, V., additional, Franchetti, Y., additional, Shulman, D., additional, Redjal, N., additional, Tabak, B., additional, Beroukhim, R., additional, Zhao, J., additional, Buonamici, S., additional, Ligon, K., additional, Kelleher, J., additional, Segal, R., additional, Canton, D., additional, Diaz, P., additional, Scott, J., additional, Hara, K., additional, Kageji, T., additional, Mizobuchi, Y., additional, Kitazato, K., additional, Okazaki, T., additional, Fujihara, T., additional, Nakajima, K., additional, Mure, H., additional, Kuwayama, K., additional, Hara, T., additional, Nagahiro, S., additional, Hill, L., additional, Botfield, H., additional, Hossain-Ibrahim, K., additional, Logan, A., additional, Cruickshank, G., additional, Liu, Y., additional, Gilbert, M., additional, Kyprianou, N., additional, Rangnekar, V., additional, Horbinski, C., additional, Hu, Y., additional, Vo, C., additional, Li, Z., additional, Ke, C., additional, Ru, N., additional, Hess, K. R., additional, Linskey, M. E., additional, Zhou, Y.-a. H., additional, Hu, F., additional, Vinnakota, K., additional, Wolf, S., additional, Kettenmann, H., additional, Jackson, P. J., additional, Larson, J. D., additional, Beckmann, D. A., additional, Moriarity, B. S., additional, Largaespada, D. A., additional, Jalali, S., additional, Agnihotri, S., additional, Singh, S., additional, Burrell, K., additional, Croul, S., additional, Zadeh, G., additional, Kang, S.-H., additional, Yu, M. O., additional, Song, N.-H., additional, Park, K.-J., additional, Chi, S.-G., additional, Chung, Y.-G., additional, Kim, S. K., additional, Kim, J. W., additional, Kim, J. Y., additional, Kim, J. E., additional, Choi, S. H., additional, Kim, T. M., additional, Lee, S.-H., additional, Kim, S.-K., additional, Park, S.-H., additional, Kim, I. H., additional, Park, C.-K., additional, Jung, H.-W., additional, Koldobskiy, M., additional, Ahmed, I., additional, Ho, G., additional, Snowman, A., additional, Raabe, E., additional, Eberhart, C., additional, Snyder, S., additional, Gugel, I., additional, Bornemann, A., additional, Pantazis, G., additional, Mack, S., additional, Shih, D., additional, Sabha, N., additional, Tatagiba, M., additional, Krischek, B., additional, Schulte, A., additional, Liffers, K., additional, Kathagen, A., additional, Riethdorf, S., additional, Westphal, M., additional, Lamszus, K., additional, Lee, J. S., additional, Xiao, J., additional, Patel, P., additional, Schade, J., additional, Wang, J., additional, Deneen, B., additional, Song, H.-R., additional, Leiss, L., additional, Gjerde, C., additional, Saed, H., additional, Rahman, A., additional, Lellahi, M., additional, Enger, P. O., additional, Leung, R., additional, Gil, O., additional, Lei, L., additional, Canoll, P., additional, Sun, S., additional, Lee, D., additional, Ho, A. S. W., additional, Pu, J. K. S., additional, Zhang, X.-q., additional, Lee, N. P., additional, Dat, P. J. R., additional, Leung, G. K. K., additional, Loetsch, D., additional, Steiner, E., additional, Holzmann, K., additional, Pirker, C., additional, Hlavaty, J., additional, Petznek, H., additional, Hegedus, B., additional, Garay, T., additional, Mohr, T., additional, Sommergruber, W., additional, Lukiw, W. J., additional, Jones, B. M., additional, Zhao, Y., additional, Bhattacharjee, S., additional, Culicchia, F., additional, Magnus, N., additional, Garnier, D., additional, Meehan, B., additional, McGraw, S., additional, Hashemi, M., additional, Lee, T. H., additional, Milsom, C., additional, Gerges, N., additional, Trasler, J., additional, Pawlinski, R., additional, Mackman, N., additional, Rak, J., additional, Maherally, Z., additional, Thorne, A., additional, An, Q., additional, Barbu, E., additional, Fillmore, H., additional, Pilkington, G., additional, Tan, S. L., additional, Tan, S., additional, Choi, S., additional, Potts, C., additional, Ford, D. A., additional, Nahle, Z., additional, Kenney, A. M., additional, Matlaf, L., additional, Khan, S., additional, Zider, A., additional, Singer, E., additional, Cobbs, C., additional, Soroceanu, L., additional, McFarland, B. C., additional, Hong, S. W., additional, Rajbhandari, R., additional, Twitty, G. B., additional, Gray, G. K., additional, Yu, H., additional, Benveniste, E. N., additional, Nozell, S. E., additional, Minata, M., additional, Kim, S., additional, Mao, P., additional, Kaushal, J., additional, Nakano, I., additional, Mizowaki, T., additional, Sasayama, T., additional, Tanaka, K., additional, Mizukawa, K., additional, Nishihara, M., additional, Nakamizo, S., additional, Tanaka, H., additional, Kohta, M., additional, Hosoda, K., additional, Kohmura, E., additional, Moeckel, S., additional, Meyer, K., additional, Leukel, P., additional, Bogdahn, U., additional, Riehmenschneider, M. J., additional, Bosserhoff, A. K., additional, Spang, R., additional, Hau, P., additional, Mukasa, A., additional, Watanabe, A., additional, Ogiwara, H., additional, Aburatani, H., additional, Mukherjee, J., additional, Obha, S., additional, See, W., additional, Pieper, R., additional, Otsuka, R., additional, Kung, D., additional, Sinha, T., additional, Meares, G., additional, Nozell, S., additional, Ott, M., additional, Litzenburger, U., additional, Rauschenbach, K., additional, Bunse, L., additional, Pusch, S., additional, Ochs, K., additional, Sahm, F., additional, Opitz, C., additional, von Deimling, A., additional, Wick, W., additional, Platten, M., additional, Peruzzi, P., additional, Read, R., additional, Fenton, T., additional, Wykosky, J., additional, Vandenberg, S., additional, Babic, I., additional, Iwanami, A., additional, Yang, H., additional, Mischel, P., additional, Thomas, J., additional, Ronellenfitsch, M. W., additional, Thiepold, A. L., additional, Harter, P. N., additional, Mittelbronn, M., additional, Steinbach, J. P., additional, Rybakova, Y., additional, Kalen, A., additional, Sarsour, E., additional, Goswami, P., additional, Silber, J., additional, Harinath, G., additional, Aldaz, B., additional, Fabius, A. W. M., additional, Turcan, S., additional, Chan, T. A., additional, Huse, J. T., additional, Sonabend, A. M., additional, Bansal, M., additional, Guarnieri, P., additional, Soderquist, C., additional, Yun, J., additional, Kennedy, B., additional, Sisti, J., additional, Bruce, S., additional, Bruce, R., additional, Shakya, R., additional, Ludwig, T., additional, Rosenfeld, S., additional, Sims, P. A., additional, Bruce, J. N., additional, Califano, A., additional, Stockhausen, M.-T., additional, Kristoffersen, K., additional, Olsen, L. S., additional, Poulsen, H. S., additional, Stringer, B., additional, Day, B., additional, Barry, G., additional, Piper, M., additional, Jamieson, P., additional, Ensbey, K., additional, Bruce, Z., additional, Richards, L., additional, Boyd, A., additional, Sufit, A., additional, Burleson, T., additional, Le, J. P., additional, Keating, A. K., additional, Sundstrom, T., additional, Varughese, J. K., additional, Harter, P., additional, Prestegarden, L., additional, Petersen, K., additional, Azuaje, F., additional, Tepper, C., additional, Ingham, E., additional, Even, L., additional, Johnson, S., additional, Skaftnesmo, K. O., additional, Lund-Johansen, M., additional, Bjerkvig, R., additional, Ferrara, K., additional, Thorsen, F., additional, Takeshima, H., additional, Yamashita, S., additional, Yokogami, K., additional, Mizuguchi, S., additional, Nakamura, H., additional, Kuratsu, J., additional, Fukushima, T., additional, Morishita, K., additional, Tang, Y., additional, Vaka, D., additional, Chen, S., additional, Ponnuswami, A., additional, Cho, Y.-J., additional, Monje, M., additional, Nakamura, T., additional, Cahill, D., additional, Tiemann, K., additional, Hedman, H., additional, Niclou, S. P., additional, Timmer, M., additional, Tjiong, R., additional, Rohn, G., additional, Goldbrunner, R., additional, Stavrinou, P., additional, Perrech, M., additional, Tokita, M., additional, Mikheev, S., additional, Sellers, D., additional, Mikheev, A., additional, Kosai, Y., additional, Rostomily, R., additional, Tritschler, I., additional, Seystahl, K., additional, Schroeder, J. J., additional, Weller, M., additional, Wade, A., additional, Robinson, A. E., additional, Phillips, J. J., additional, Gong, Y., additional, Ma, Y., additional, Cheng, Z., additional, Thompson, R., additional, Fan, Q.-W., additional, Cheng, C., additional, Gustafson, W., additional, Charron, E., additional, Zipper, P., additional, Wong, R., additional, Chen, J., additional, Lau, J., additional, Knobbe-Thosen, C., additional, Jura, N., additional, Reifenberger, G., additional, Shokat, K., additional, Weiss, W., additional, Wu, S., additional, Hu, J., additional, Taylor, T., additional, Villa, G. R., additional, Mischel, P. S., additional, Gonias, S. L., additional, Yamashita, D., additional, Kondo, T., additional, Takahashi, H., additional, Inoue, A., additional, Kohno, S., additional, Harada, H., additional, Ohue, S., additional, Ohnishi, T., additional, Li, P., additional, Ng, J., additional, Yuelling, L., additional, Du, F., additional, Curran, T., additional, Yang, Z.-j., additional, Zhu, D., additional, Castellino, R. C., additional, Van Meir, E. G., additional, Begum, G., additional, Wang, Q., additional, Yang, S.-S., additional, Lin, S.-H., additional, and Kahle, K., additional

Published
2013
Full Text
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8. Mutations du gène du récepteur à l'ACTH et syndrome familial de déficit en glucocorticoïdes

Author

Naville, D., Barjhoux, L., Jaillard, C., Faury, D., Despert, F., Esteva, B., Durand, P., Saez, J., Bégeot, Martine, ProdInra, Migration, Communications Cellulaires et Différenciation (CCD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Institut National de la Recherche Agronomique (INRA)

Subjects
[SDV] Life Sciences [q-bio], [SDV]Life Sciences [q-bio]
Published
1996

9. HIGH GRADE GLIOMAS

Author

Leonard, A., primary, Wolff, J., additional, Sengupta, R., additional, Marassa, J., additional, Piwnica-Worms, D., additional, Rubin, J., additional, Pollack, I., additional, Jakacki, R., additional, Butterfield, L., additional, Okada, H., additional, Fangusaro, J., additional, Warren, K. E., additional, Mullins, C., additional, Jurgen, P., additional, Julia, S., additional, Friedrich, C. C., additional, Keir, S., additional, Saling, J., additional, Roskoski, M., additional, Friedman, H., additional, Bigner, D., additional, Moertel, C., additional, Olin, M., additional, Dahlheimer, T., additional, Gustafson, M., additional, Sumstad, D., additional, McKenna, D., additional, Low, W., additional, Nascene, D., additional, Dietz, A., additional, Ohlfest, J., additional, Sturm, D., additional, Witt, H., additional, Hovestadt, V., additional, Quan, D. A. K., additional, Jones, D. T. W., additional, Konermann, C., additional, Pfaff, E., additional, Korshunov, A., additional, Rizhova, M., additional, Milde, T., additional, Witt, O., additional, Zapatka, M., additional, Collins, V. P., additional, Kool, M., additional, Reifenberger, G., additional, Lichter, P., additional, Lindroth, A. M., additional, Plass, C., additional, Jabado, N., additional, Pfister, S. M., additional, Pizer, B., additional, Salehzadeh, A., additional, Brodbelt, A., additional, Mallucci, C., additional, Brassesco, M., additional, Pezuk, J., additional, Morales, A., additional, de Oliveira, J., additional, Roberto, G., additional, Umezawa, K., additional, Valera, E., additional, Rego, E., additional, Scrideli, C., additional, Tone, L., additional, Veringa, S. J. E., additional, Van Vuurden, D. G., additional, Wesseling, P., additional, Vandertop, W. P., additional, Noske, D. P., additional, Wurdinger, T., additional, Kaspers, G. J. L., additional, Hulleman, E., additional, Wright, K., additional, Broniscer, A., additional, Bendel, A., additional, Bowers, D., additional, Crawford, J., additional, Fisher, P., additional, Hassall, T., additional, Armstrong, G., additional, Baker, J., additional, Qaddoumi, I., additional, Robinson, G., additional, Wetmore, C., additional, Klimo, P., additional, Boop, F., additional, Onar-Thomas, A., additional, Ellison, D., additional, Gajjar, A., additional, Cruz, O., additional, de Torres, C., additional, Sunol, M., additional, Rodriguez, E., additional, Alonso, L., additional, Parareda, A., additional, Cardesa, T., additional, Salvador, H., additional, Celis, V., additional, Guillen, A., additional, Garcia, G., additional, Muchart, J., additional, Trampal, C., additional, Martin, M. L., additional, Rebollo, M., additional, Mora, J., additional, Piotrowski, A., additional, Kowalska, A., additional, Coyle, P., additional, Smith, S., additional, Rogers, H., additional, Macarthur, D., additional, Grundy, R., additional, Puccetti, D., additional, Salamat, S., additional, Kennedy, T., additional, Patel, N., additional, Bradley, K., additional, Casey, K., additional, Iskandar, B., additional, Nakano, Y., additional, Okada, K., additional, Osugi, Y., additional, Yamasaki, K., additional, Fujisaki, H., additional, Fukushima, H., additional, Inoue, T., additional, Matsusaka, Y., additional, Sakamoto, H., additional, Hara, J., additional, De Vleeschouwer, S., additional, Ardon, H., additional, Van Calenbergh, F., additional, Sciot, R., additional, Wilms, G., additional, Van Loon, J., additional, Goffin, J., additional, Van Gool, S., additional, Rusinak, D., additional, Knight, P., additional, Onel, K., additional, Wargowski, D., additional, Stettner, A., additional, Al-Ghafari, A., additional, Punjaruk, W., additional, Coyle, B., additional, Kerr, I., additional, Xipell, E., additional, Rodriguez, M., additional, Gonzalez-Huarriz, M., additional, Tunon, M. T., additional, Zazpe, I., additional, Tejada-Solis, S., additional, Diez-Valle, R., additional, Fueyo, J., additional, Gomez-Manzano, C., additional, Alonso, M. M., additional, Pastakia, D., additional, McCully, C., additional, Murphy, R., additional, Bacher, J., additional, Thomas, M., additional, Steffen-Smith, E., additional, Saleem, K., additional, Waldbridge, S., additional, Widemann, B., additional, Warren, K., additional, Miele, E., additional, Buttarelli, F., additional, Arcella, A., additional, Begalli, F., additional, Po, A., additional, Baldi, C., additional, Carissimo, G., additional, Antonelli, M., additional, Donofrio, V., additional, Morra, I., additional, Nozza, P., additional, Gulino, A., additional, Giangaspero, F., additional, Ferretti, E., additional, Elens, I., additional, Pauwels, F., additional, Fritzell, S., additional, Eberstal, S., additional, Sanden, E., additional, Visse, E., additional, Darabi, A., additional, Siesjo, P., additional, McDonald, P., additional, Wrogemann, J., additional, Krawitz, S., additional, Del Bigio, M., additional, Eisenstat, D., additional, Kwiecien, R., additional, Pietsch, T., additional, Faldum, A., additional, Kortmann, R.-D., additional, Warmuth-Metz, M., additional, Rutkowski, S., additional, Slavc, I., additional, Kramm, C. M., additional, Uparkar, U., additional, Geyer, R., additional, Ermoian, R., additional, Ellenbogen, R., additional, Leary, S., additional, Triscott, J., additional, Hu, K., additional, Fotovati, A., additional, Yip, S., additional, Kast, R., additional, Toyota, B., additional, Dunn, S., additional, Hegde, M., additional, Corder, A., additional, Chow, K., additional, Mukherjee, M., additional, Ashoori, A., additional, Brawley, V., additional, Heslop, H., additional, Gottschalk, S., additional, Yvon, E., additional, Ahmed, N., additional, Wong, T.-T., additional, Yang, F.-Y., additional, Lu, M., additional, Liang, H.-F., additional, Wang, H.-E., additional, Liu, R.-S., additional, Teng, M.-C., additional, Yen, C.-C., additional, Agnihotri, S., additional, Ternamian, C., additional, Jones, C., additional, Zadeh, G., additional, Rutka, J., additional, Hawkins, C., additional, Filipek, I., additional, Drogosiewicz, M., additional, Perek-Polnik, M., additional, Swieszkowska, E., additional, Baginska, B. D., additional, Jurkiewicz, E., additional, Perek, D., additional, Kuehn, A., additional, Falkenstein, F., additional, Gnekow, A., additional, Kramm, C., additional, Brooks, M. D., additional, Jackson, E., additional, Mitra, R. D., additional, Rubin, J. B., additional, Liu, X.-Y., additional, Schwartzentruber, J., additional, Fontebasso, A. M., additional, Quang, D.-A. K., additional, Albrecht, S., additional, Dong, Z., additional, Siegel, P., additional, Von Diemling, A., additional, Faury, D., additional, Tabori, U., additional, Majewski, J., additional, Lulla, R., additional, Echevarria, M., additional, Alden, T., additional, DiPatri, A., additional, Tomita, T., additional, Goldman, S., additional, Lin, T., additional, Merchant, T. E., additional, Kocak, M., additional, Panandiker, A. P., additional, Armstrong, G. T., additional, Gielen, G. H., additional, Muehlen, A. z., additional, Hubert, C., additional, Ding, Y., additional, Toledo, C., additional, Paddison, P., additional, Olson, J., additional, Nandhabalan, M., additional, Bjerke, L., additional, Bax, D., additional, Carvalho, D., additional, Bajrami, I., additional, Ashworth, A., additional, Lord, C., additional, Hargrave, D., additional, Reis, R., additional, Workman, P., additional, Little, S., additional, Popov, S., additional, Jury, A., additional, Burford, A., additional, Doey, L., additional, Al-Sarraj, S., additional, Jurgensmeier, J., additional, Chen, L., additional, Kozarewa, I., additional, Baker, S., additional, Perryman, L., additional, Box, G., additional, Raynaud, F., additional, Eccles, S., additional, Viana-Pereira, M., additional, Pereira, M., additional, Forshew, T., additional, Tatevossian, R., additional, Sheer, D., additional, Pimental, J., additional, Pires, M., additional, Sarkar, C., additional, Jha, P., additional, Patrick, I. R. P., additional, Somasundaram, K., additional, Pathak, P., additional, Sharma, M. C., additional, Suri, V., additional, Suri, A., additional, Gerges, N., additional, Haque, T., additional, Nantel, A., additional, Lee, C., additional, Chen, J., additional, Venugopal, C., additional, Singhal, A., additional, Dunham, C., additional, Kerr, J., additional, Verreault, M., additional, Wakimoto, H., additional, Jayanthan, A., additional, Narendran, A., additional, Singh, S., additional, Giraud, G., additional, Holm, S., additional, Gustavsson, B., additional, Kizyma, R., additional, Kizyma, Z., additional, Dvornyak, L., additional, Kotsay, B., additional, Epari, S., additional, Sharma, P., additional, Gurav, M., additional, Gupta, T., additional, Shetty, P., additional, Moiyadi, A., additional, Kane, S., additional, and Jalali, R., additional

Published
2012
Full Text
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10. ANGIOGENESIS AND INVASION

Author

Hu, Y.-L., primary, De Lay, M., additional, Rose, S. D., additional, Carbonell, W. S., additional, Aghi, M. K., additional, Hu, Y.-L., additional, Paquette, J., additional, Tokuyasu, T., additional, Tsao, S., additional, Chaumeil, M., additional, Ronen, S., additional, Matlaf, L. A., additional, Soroceanu, L., additional, Cobbs, C., additional, Matlaf, L., additional, Harkins, L., additional, Garzon-Muvdi, T., additional, Rhys, C. a., additional, Smith, C., additional, Kim, D.-H., additional, Kone, L., additional, Farber, H., additional, An, S., additional, Levchenko, A., additional, Quinones-Hinojosa, A., additional, Lemke, D., additional, Pfenning, P.-N., additional, Sahm, F., additional, Klein, A.-C., additional, Kempf, T., additional, Schnolzer, M., additional, Platten, M., additional, Wick, W., additional, Smith, S. J., additional, Rahman, R., additional, Rahman, C., additional, Barrow, J., additional, Macarthur, D., additional, Rose, F., additional, Grundy, R. G., additional, Kaley, T. J., additional, Huse, J., additional, Karimi, S., additional, Rosenblum, M., additional, Omuro, A., additional, DeAngelis, L. M., additional, de Groot, J. F., additional, Kong, L.-Y., additional, Wei, J., additional, Wang, T., additional, Piao, Y., additional, Liang, J., additional, Fuller, G. N., additional, Qiao, W., additional, Heimberger, A. B., additional, Jhaveri, N., additional, Cho, H., additional, Torres, S., additional, Wang, W., additional, Schonthal, A., additional, Petasis, N., additional, Louie, S. G., additional, Hofman, F., additional, Chen, T. C., additional, Yamada, R., additional, Sumual, S., additional, Buljan, V., additional, Bennett, M. R., additional, McDonald, K. L., additional, Weiler, M., additional, Thiepold, A.-L., additional, Jestaedt, L., additional, Gronych, J., additional, Dittmann, L. M., additional, Jugold, M., additional, Kosch, M., additional, Combs, S. E., additional, von Deimling, A., additional, Weller, M., additional, Bendszus, M., additional, Kwiatkowska, A., additional, Paulino, V., additional, Tran, N. L., additional, Symons, M., additional, Stockham, A. L., additional, Borden, E., additional, Peereboom, D., additional, Hu, Y., additional, Chaturbedi, A., additional, Hamamura, M., additional, Mark, E., additional, Zhou, Y.-H., additional, Abbadi, S., additional, Guerrero-Cazares, H., additional, Pistollato, F., additional, Smith, C. L., additional, Ruff, W., additional, Puppa, A. D., additional, Basso, G., additional, Monje, M., additional, Freret, M. E., additional, Masek, M., additional, Fisher, P. G., additional, Haddix, T., additional, Vogel, H., additional, Kijima, N., additional, Hosen, N., additional, Kagawa, N., additional, Hashimoto, N., additional, Fujimoto, Y., additional, Kinoshita, M., additional, Sugiyama, H., additional, Yoshimine, T., additional, Anneke, N., additional, Bob, H., additional, Pieter, W., additional, Arend, H., additional, William, L., additional, Eoli, M., additional, Calleri, A., additional, Cuppini, L., additional, Anghileri, E., additional, Pellegatta, S., additional, Prodi, E., additional, Bruzzone, M. G., additional, Bertolini, F., additional, Finocchiaro, G., additional, Zhu, D., additional, Hunter, S. B., additional, Vertino, P. M., additional, Van Meir, E. G., additional, Cork, S. M., additional, Kaur, B., additional, Cooper, L., additional, Saltz, J. H., additional, Sandberg, E. M., additional, Burrell, K., additional, Hill, R., additional, Zadeh, G., additional, Parker, J. J., additional, Dionne, K., additional, Massarwa, R., additional, Klaassen, M., additional, Niswander, L., additional, Kleinschmidt-DeMasters, B. K., additional, Waziri, A., additional, Jalali, S., additional, Wataya, T., additional, Salehi, F., additional, Croul, S., additional, Gentili, F., additional, Foltz, W., additional, Lee, J.-I., additional, Agnihorti, S., additional, Menard, C., additional, Chung, C., additional, Schonthal, A. H., additional, Hofman, F. M., additional, Elena, P., additional, Faivre, G., additional, Demopoulos, A., additional, Taillibert, S., additional, Kirsch, M., additional, Martin, K. D., additional, Bertram, A., additional, uckermann, O., additional, Leipnitz, E., additional, Weigel, P., additional, Temme, A., additional, Schackert, G., additional, Geiger, K., additional, Gerstner, E., additional, Jennings, D., additional, Chi, A. S., additional, Plotkin, S., additional, Kwon, S. J., additional, Pinho, M., additional, Polaskova, P., additional, Batchelor, T. T., additional, Sorensen, A. G., additional, Hossain, M. B., additional, Gururaj, A. E., additional, Cortes-Santiago, N., additional, Gabrusiewicz, K., additional, Yung, W. K. A., additional, Fueyo, J., additional, Gomez-Manzano, C., additional, Gil, O. D., additional, Noticewala, S., additional, Ivkovic, S., additional, Esencay, M., additional, Zagzagg, D., additional, Rosenfeld, S., additional, Bruce, J. N., additional, Canoll, P., additional, Chang, J. H., additional, Seol, H. J., additional, Weeks, A., additional, Smith, C. A., additional, Rutka, J. T., additional, Georges, J., additional, Samuelson, G., additional, Misra, A., additional, Joy, A., additional, Huang, Y., additional, McQuilkin, M., additional, Yoshihiro, A., additional, Carpenter, D., additional, Butler, L., additional, Feuerstein, B., additional, Murphy, S. F., additional, Vaghaiwalla, T., additional, Wotoczek-Obadia, M., additional, Albright, R., additional, Mack, D., additional, Lawn, S., additional, Henderson, F., additional, Jung, M., additional, Dakshanamurthy, S., additional, Brown, M., additional, Forsyth, P., additional, Brem, S., additional, Sadr, M. S., additional, Maret, D., additional, Sadr, E. S., additional, Siu, V., additional, Alshami, J., additional, Trinh, G., additional, Denault, J.-S., additional, Faury, D., additional, Jabado, N., additional, Nantel, A., additional, and Del Maestro, R., additional

Published
2011
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11. Angiogenesis and Invasion

Author

Fishman, R. A., primary, Happ, E., additional, Stevens, T., additional, Kunschner, L., additional, Jaworski, D. M., additional, Stradecki, H. M., additional, Penar, P. L., additional, Pendlebury, W. W., additional, Pennington, C. J., additional, Edwards, D. R., additional, Broaddus, W. C., additional, Fillmore, H. L., additional, Mukherjee, J., additional, Hawkins, C., additional, Guha, A., additional, Pioli, P. D., additional, Milani, S., additional, Linskey, M. E., additional, Zhou, Y.-H., additional, Marchetti, V., additional, Barnett, F., additional, Wang, M., additional, Scheppke, L., additional, Sanchez-Cespedes, J., additional, De Rossi, C., additional, Nemerow, G., additional, Torbett, B., additional, Friedlander, M., additional, Goldlust, S. A., additional, Singer, S., additional, DeAngelis, L. M., additional, Lassman, A. B., additional, Nolan, C. P., additional, Yang, S.-H., additional, Lee, S. W., additional, Chen, Z.-p., additional, Liu, X.-m., additional, Wojton, J. A., additional, Chu, Z., additional, Qi, X., additional, Kaur, B., additional, Hu, Y., additional, Siegel, E., additional, Ro, D. I., additional, Marlon, S., additional, Hsu, N., additional, Milani, S. N., additional, Mohan, S., additional, Yu, L., additional, Hess, K. R., additional, Liu, Y., additional, Carson-Walter, E., additional, Walter, K., additional, Raghu, H., additional, Gondi, C. S., additional, Gujrati, M., additional, Dinh, D. H., additional, Rao, J. S., additional, Narayana, A., additional, Kunnakkat, S. D., additional, Medabalmi, P., additional, Golfinos, J., additional, Parker, E., additional, Knopp, E., additional, Zagzag, D., additional, Gruber, D., additional, Gruber, M. L., additional, Burrell, K., additional, Jelveh, S., additional, Lindsey, P., additional, Hill, R., additional, Zadeh, G., additional, Ivkovic, S., additional, Beadle, C., additional, Massey, S. C., additional, Swanson, K. R., additional, Canoll, P., additional, Rosenfeld, S. S., additional, McAllister, S., additional, Soroceanu, L., additional, Pakdel, A., additional, Limbad, C., additional, Adrados, I., additional, Desprez, P.-Y., additional, Nakada, M., additional, Nambu, E., additional, Furuyama, N., additional, Yoshida, Y., additional, Kita, D., additional, Hayashi, Y., additional, Hamada, J.-i., additional, Seyed Sadr, M., additional, Maret, D., additional, Seyed Sadr, E., additional, Siu, V., additional, Alshami, J., additional, Denault, J.-S., additional, Faury, D., additional, Jabado, N., additional, Nantel, A., additional, Del Maestro, R., additional, Perretta, D., additional, Nagaiah, G., additional, Almubarak, M., additional, Torres-Trejo, A., additional, Newton,, M., additional, Willey, P., additional, Altaha, R., additional, Murphy, S. F., additional, Banasiak, M., additional, Yee, G.-T., additional, Wotoczek-Obadia, M., additional, Tran, Y., additional, Prak, A., additional, Albright, R., additional, Mullan, M., additional, Paris, D., additional, Brem, S., additional, Yang, Y.-P., additional, Ennis, M., additional, Tran, N., additional, Symons, M., additional, Najbauer, J., additional, Huszthy, P. C., additional, Garcia, E., additional, Metz, M. Z., additional, Gutova, M., additional, Frank, R. T., additional, Miletic, H., additional, Glackin, C. A., additional, Barish, M. E., additional, Bjerkvig, R., additional, Aboody, K. S., additional, Clump, D. A., additional, Engh, J. A., additional, Mintz, A. H., additional, Cunnick, J., additional, Flynn, D. C., additional, Clark, A. J., additional, Butowski, N. A., additional, Chang, S. M., additional, Prados, M. D., additional, Clarke, J., additional, Polley, M.-Y. C., additional, Sughrue, M. E., additional, McDermott, M. W., additional, Parsa, A. T., additional, Berger, M. S., additional, Aghi, M. K., additional, Megyesi, J. F., additional, Costello, P., additional, Macdonald, W., additional, Dyer, E., additional, Macdonald, D., additional, Hammond, R., additional, Kalache, Y., additional, Easaw, J., additional, McIntyre, J., additional, Williams, S. C., additional, Karajannis, M. A., additional, Chiriboga, L., additional, von Deimling, A., additional, Ajlan, A., additional, Husaine, S., additional, Petrecca, K., additional, Magnus, N., additional, Garnier, D., additional, Meehan, B., additional, and Rak, J., additional

Published
2010
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12. Duplication of 7q34 is specific to juvenile pilocytic astrocytomas and a hallmark of cerebellar and optic pathway tumours

Author

Jacob, K, primary, Albrecht, S, additional, Sollier, C, additional, Faury, D, additional, Sader, E, additional, Montpetit, A, additional, Serre, D, additional, Hauser, P, additional, Garami, M, additional, Bognar, L, additional, Hanzely, Z, additional, Montes, J L, additional, Atkinson, J, additional, Farmer, J-P, additional, Bouffet, E, additional, Hawkins, C, additional, Tabori, U, additional, and Jabado, N, additional

Published
2009
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18. FOXR2 Targets LHX6+/DLX+ Neural Lineages to Drive Central Nervous System Neuroblastoma.

Author

Jessa S, De Cola A, Chandarana B, McNicholas M, Hébert S, Ptack A, Faury D, Tsai JW, Korshunov A, Phoenix TN, Ellezam B, Jones DTW, Taylor MD, Bandopadhayay P, Pathania M, Jabado N, and Kleinman CL

Subjects
Animals, Mice, Humans, Cell Lineage, Nerve Tissue Proteins genetics, Nerve Tissue Proteins metabolism, Neurons metabolism, Neurons pathology, Gene Expression Regulation, Neoplastic, Brain Neoplasms pathology, Brain Neoplasms metabolism, Brain Neoplasms genetics, Forkhead Transcription Factors metabolism, Forkhead Transcription Factors genetics, Neuroblastoma pathology, Neuroblastoma genetics, Neuroblastoma metabolism, LIM-Homeodomain Proteins metabolism, LIM-Homeodomain Proteins genetics, Transcription Factors metabolism, Transcription Factors genetics
Abstract

Central nervous system neuroblastoma with forkhead box R2 (FOXR2) activation (NB-FOXR2) is a high-grade tumor of the brain hemispheres and a newly identified molecular entity. Tumors express dual neuronal and glial markers, leading to frequent misdiagnoses, and limited information exists on the role of FOXR2 in their genesis. To identify their cellular origins, we profiled the transcriptomes of NB-FOXR2 tumors at the bulk and single-cell levels and integrated these profiles with large single-cell references of the normal brain. NB-FOXR2 tumors mapped to LHX6+/DLX+ lineages derived from the medial ganglionic eminence, a progenitor domain in the ventral telencephalon. In vivo prenatal Foxr2 targeting to the ganglionic eminences in mice induced postnatal cortical tumors recapitulating human NB-FOXR2-specific molecular signatures. Profiling of FOXR2 binding on chromatin in murine models revealed an association with ETS transcriptional networks, as well as direct binding of FOXR2 at key transcription factors that coordinate initiation of gliogenesis. These data indicate that NB-FOXR2 tumors originate from LHX6+/DLX+ interneuron lineages, a lineage of origin distinct from that of other FOXR2-driven brain tumors, highlight the susceptibility of ventral telencephalon-derived interneurons to FOXR2-driven oncogenesis, and suggest that FOXR2-induced activation of glial programs may explain the mixed neuronal and oligodendroglial features in these tumors. More broadly, this work underscores systematic profiling of brain development as an efficient approach to orient oncogenic targeting for in vivo modeling, critical for the study of rare tumors and development of therapeutics. Significance: Profiling the developing brain enabled rationally guided modeling of FOXR2-activated CNS neuroblastoma, providing a strategy to overcome the heterogeneous origins of pediatric brain tumors that hamper tumor modeling and therapy development. See related commentary by Orr, p. 195., (©2024 The Authors; Published by the American Association for Cancer Research.)

Published
2025
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19. Immune landscape of oncohistone-mutant gliomas reveals diverse myeloid populations and tumor-promoting function.

Author

Andrade AF, Annett A, Karimi E, Topouza DG, Rezanejad M, Liu Y, McNicholas M, Gonzalez Santiago EG, Llivichuzhca-Loja D, Gehlhaar A, Jessa S, De Cola A, Chandarana B, Russo C, Faury D, Danieau G, Puligandla E, Wei Y, Zeinieh M, Wu Q, Hebert S, Juretic N, Nakada EM, Krug B, Larouche V, Weil AG, Dudley RWR, Karamchandani J, Agnihotri S, Quail DF, Ellezam B, Konnikova L, Walsh LA, Pathania M, Kleinman CL, and Jabado N

Subjects
Animals, Mice, Humans, Cell Line, Tumor, Disease Models, Animal, Mice, Inbred C57BL, Gene Expression Regulation, Neoplastic, Single-Cell Analysis, Glioma genetics, Glioma immunology, Glioma pathology, Tumor Microenvironment immunology, Tumor Microenvironment genetics, Myeloid Cells metabolism, Myeloid Cells immunology, Histones metabolism, Histones genetics, Brain Neoplasms genetics, Brain Neoplasms immunology, Brain Neoplasms pathology, Mutation
Abstract

Histone H3-mutant gliomas are deadly brain tumors characterized by a dysregulated epigenome and stalled differentiation. In contrast to the extensive datasets available on tumor cells, limited information exists on their tumor microenvironment (TME), particularly the immune infiltrate. Here, we characterize the immune TME of H3.3K27M and G34R/V-mutant gliomas, and multiple H3.3K27M mouse models, using transcriptomic, proteomic and spatial single-cell approaches. Resolution of immune lineages indicates high infiltration of H3-mutant gliomas with diverse myeloid populations, high-level expression of immune checkpoint markers, and scarce lymphoid cells, findings uniformly reproduced in all H3.3K27M mouse models tested. We show these myeloid populations communicate with H3-mutant cells, mediating immunosuppression and sustaining tumor formation and maintenance. Dual inhibition of myeloid cells and immune checkpoint pathways show significant therapeutic benefits in pre-clinical syngeneic mouse models. Our findings provide a valuable characterization of the TME of oncohistone-mutant gliomas, and insight into the means for modulating the myeloid infiltrate for the benefit of patients., (© 2024. The Author(s).)

Published
2024
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20. Recurrent primary intracranial sarcoma, DICER1-mutant in a pediatric patient with DICER1 syndrome: the importance of molecular testing.

Author

Lachance A, Dimentberg E, Huang S, Bergeron-Gravel S, Bouffet É, Fonseca A, Crevier L, Saikali S, Bourget C, Giannakouros P, Faury D, Jabado N, Foulkes WD, Larouche V, and Renzi S

Subjects
Humans, Female, Mutation genetics, Child, Ribonuclease III genetics, DEAD-box RNA Helicases genetics, Brain Neoplasms genetics, Brain Neoplasms diagnostic imaging, Neoplasm Recurrence, Local genetics, Sarcoma genetics
Abstract

Pediatric intracranial sarcomas are rare, aggressive tumors with a poor prognosis in general. Here we report the case of a child who was initially diagnosed with a primary intracranial sarcoma, DICER1-mutant; subsequent genetic analyses confirmed a pathogenic germline DICER1 mutation. She received multimodal standard treatments consisting of surgery, radiotherapy and chemotherapy. The tumor recurred 2.5 years later within the surgical cavity. Following the gross tumor resection of this new lesion, the same multimodal standard approach was used. From a molecular perspective, evidence of hyperactivation of the MAPK-kinase pathway with a pathogenic KRAS mutation at both diagnosis and recurrence was present. The patient is currently in remission, 18 months post-end of treatment., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Published
2024
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21. Comprehensive Genomic Analysis of Cemento-Ossifying Fibroma.

Author

Gomez RS, El Mouatani A, Duarte-Andrade FF, Pereira TDSF, Guimarães LM, Gayden T, Faury D, Nakada EM, Langlois S, Sinnett D, de Castro WH, Diniz MG, Jabado N, and Gomes CC

Subjects
Humans, Genomics, Protein Tyrosine Phosphatases, Non-Receptor, Adaptor Proteins, Signal Transducing, Ubiquitin-Protein Ligases, Cementoma pathology, Fibroma, Ossifying genetics, Odontogenic Tumors pathology
Abstract

Cemento-ossifying fibroma (COF) of the jaws is currently classified as a benign mesenchymal odontogenic tumor, and only targeted approaches have been used to assess its genetic alterations. A minimal proportion of COFs harbor CDC73 somatic mutations, and copy number alterations (CNAs) involving chromosomes 7 and 12 have recently been reported in a small proportion of cases. However, the genetic background of COFs remains obscure. We used a combination of whole-exome sequencing and RNA sequencing to assess somatic mutations, fusion transcripts, and CNAs in a cohort of 12 freshly collected COFs. No recurrent fusions have been identified among the 5 cases successfully analyzed by RNA sequencing, with in-frame fusions being detected in 2 cases (MARS1::GOLT1B and PARG::BMS1 in one case and NCLN::FZR1 and NFIC::SAMD1 in the other case) and no candidate fusions identified for the remaining 3 cases. No recurrent pathogenic mutations were detected in the 11 cases that had undergone whole-exome sequencing. A KRAS p.L19F missense variant was detected in one case, and 2 CDC73 deletions were detected in another case. The other variants were of uncertain significance and included variants in PC, ACTB, DOK6, HACE1, and COL1A2 and previously unreported variants in PTPN14, ATP5F1C, APOBEC1, HDAC5, ATF7IP, PARP2, and ACTR3B. The affected genes do not clearly converge on any signaling pathway. CNAs were detected in 5/11 cases (45%), with copy gains involving chromosome 12 occurring in 3/11 cases (27%). In conclusion, no recurrent fusions or pathogenic variants have been detected in the present COF cohort, with copy gains involving chromosome 12 occurring in 27% of cases., (Copyright © 2023 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

Published
2024
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22. Bevacizumab in the Treatment of Refractory Brain Edema in High-grade Glioma.

Author

Alsahlawi AK, Michaud-Couture C, Lachance A, Bergeron-Gravel S, Létourneau M, Bourget C, Gould PV, Giannakouros P, Nakada EM, Faury D, Crevier L, Bouffet É, Jabado N, Larouche V, and Renzi S

Subjects
Male, Humans, Adolescent, Bevacizumab therapeutic use, Angiogenesis Inhibitors therapeutic use, Brain Edema drug therapy, Brain Edema etiology, Brain Neoplasms complications, Brain Neoplasms drug therapy, Brain Neoplasms pathology, Glioma complications, Glioma drug therapy, Glioma pathology, Radiation Injuries
Abstract

We report the case of a 14-year-old boy with a steroid-dependent refractory tumor whose longstanding dexamethasone treatment was successfully discontinued after a course of bevacizumab. The use of bevacizumab despite the absence of clear evidence of radionecrosis allowed a significant decrease in the amount of the brain edema., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Published
2024
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23. Phase I trial of panobinostat in children with diffuse intrinsic pontine glioma: A report from the Pediatric Brain Tumor Consortium (PBTC-047).

Author

Monje M, Cooney T, Glod J, Huang J, Peer CJ, Faury D, Baxter P, Kramer K, Lenzen A, Robison NJ, Kilburn L, Vinitsky A, Figg WD, Jabado N, Fouladi M, Fangusaro J, Onar-Thomas A, Dunkel IJ, and Warren KE

Subjects
Child, Humans, Panobinostat pharmacokinetics, Diffuse Intrinsic Pontine Glioma drug therapy, Posterior Leukoencephalopathy Syndrome, Glioma drug therapy, Glioma pathology, Thrombocytopenia, Neutropenia, Brain Stem Neoplasms drug therapy, Brain Stem Neoplasms pathology
Abstract

Background: Diffuse intrinsic pontine glioma (DIPG) is a lethal childhood cancer with median survival of less than 1 year. Panobinostat is an oral multihistone deacetylase inhibitor with preclinical activity in DIPG models. Study objectives were to determine safety, tolerability, maximum tolerated dose (MTD), toxicity profile, and pharmacokinetics of panobinostat in children with DIPG., Patients and Methods: In stratum 1, panobinostat was administered 3 days per week for 3 weeks on, 1 week off to children with progressive DIPG, with dose escalation following a two-stage continual reassessment method. After this MTD was determined, the study was amended to evaluate the MTD in children with nonprogressive DIPG/Diffuse midline glioma (DMG) (stratum 2) on an alternate schedule, 3 days a week every other week in an effort to escalate the dose., Results: For stratum 1, 19 subjects enrolled with 17/19 evaluable for dose-finding. The MTD was 10 mg/m2/dose. Dose-limiting toxicities included thrombocytopenia and neutropenia. Posterior reversible encephalopathy syndrome was reported in 1 patient. For stratum 2, 34 eligible subjects enrolled with 29/34 evaluable for dose finding. The MTD on this schedule was 22 mg/m2/dose. DLTs included thrombocytopenia, neutropenia, neutropenia with grade 4 thrombocytopenia, prolonged intolerable nausea, and increased ALT., Conclusions: The MTD of panobinostat is 10 mg/m2/dose administered 3 times per week for 3 weeks on/1 week off in children with progressive DIPG/DMG and 22 mg/m2/dose administered 3 times per week for 1 week on/1 week off when administered in a similar population preprogression. The most common toxicity for both schedules was myelosuppression., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Published
2023
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24. H3K27me3 spreading organizes canonical PRC1 chromatin architecture to regulate developmental programs.

Author

Krug B, Hu B, Chen H, Ptack A, Chen X, Gretarsson KH, Deshmukh S, Kabir N, Andrade AF, Jabbour E, Harutyunyan AS, Lee JJY, Hulswit M, Faury D, Russo C, Xu X, Johnston MJ, Baguette A, Dahl NA, Weil AG, Ellezam B, Dali R, Blanchette M, Wilson K, Garcia BA, Soni RK, Gallo M, Taylor MD, Kleinman CL, Majewski J, Jabado N, and Lu C

Abstract

Polycomb Repressive Complex 2 (PRC2)-mediated histone H3K27 tri-methylation (H3K27me3) recruits canonical PRC1 (cPRC1) to maintain heterochromatin. In early development, polycomb-regulated genes are connected through long-range 3D interactions which resolve upon differentiation. Here, we report that polycomb looping is controlled by H3K27me3 spreading and regulates target gene silencing and cell fate specification. Using glioma-derived H3 Lys-27-Met (H3K27M) mutations as tools to restrict H3K27me3 deposition, we show that H3K27me3 confinement concentrates the chromatin pool of cPRC1, resulting in heightened 3D interactions mirroring chromatin architecture of pluripotency, and stringent gene repression that maintains cells in progenitor states to facilitate tumor development. Conversely, H3K27me3 spread in pluripotent stem cells, following neural differentiation or loss of the H3K36 methyltransferase NSD1, dilutes cPRC1 concentration and dissolves polycomb loops. These results identify the regulatory principles and disease implications of polycomb looping and nominate histone modification-guided distribution of reader complexes as an important mechanism for nuclear compartment organization., Highlights: The confinement of H3K27me3 at PRC2 nucleation sites without its spreading correlates with increased 3D chromatin interactions.The H3K27M oncohistone concentrates canonical PRC1 that anchors chromatin loop interactions in gliomas, silencing developmental programs.Stem and progenitor cells require factors promoting H3K27me3 confinement, including H3K36me2, to maintain cPRC1 loop architecture.The cPRC1-H3K27me3 interaction is a targetable driver of aberrant self-renewal in tumor cells.

Published
2023
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25. A Compendium of Syngeneic, Transplantable Pediatric High-Grade Glioma Models Reveals Subtype-Specific Therapeutic Vulnerabilities.

Author

McNicholas M, De Cola A, Bashardanesh Z, Foss A, Lloyd CB, Hébert S, Faury D, Andrade AF, Jabado N, Kleinman CL, and Pathania M

Subjects
Animals, Mice, Histones metabolism, Gene Expression Regulation, Neoplastic, Brain pathology, Mutation, Glioma drug therapy, Glioma genetics, Brain Neoplasms drug therapy, Brain Neoplasms genetics, Brain Neoplasms metabolism
Abstract

Pediatric high-grade gliomas (pHGG) are lethal, incurable brain tumors frequently driven by clonal mutations in histone genes. They often harbor a range of additional genetic alterations that correlate with different ages, anatomic locations, and tumor subtypes. We developed models representing 16 pHGG subtypes driven by different combinations of alterations targeted to specific brain regions. Tumors developed with varying latencies and cell lines derived from these models engrafted in syngeneic, immunocompetent mice with high penetrance. Targeted drug screening revealed unexpected selective vulnerabilities-H3.3G34R/PDGFRAC235Y to FGFR inhibition, H3.3K27M/PDGFRAWT to PDGFRA inhibition, and H3.3K27M/PDGFRAWT and H3.3K27M/PPM1DΔC/PIK3CAE545K to combined inhibition of MEK and PIK3CA. Moreover, H3.3K27M tumors with PIK3CA, NF1, and FGFR1 mutations were more invasive and harbored distinct additional phenotypes, such as exophytic spread, cranial nerve invasion, and spinal dissemination. Collectively, these models reveal that different partner alterations produce distinct effects on pHGG cellular composition, latency, invasiveness, and treatment sensitivity., Significance: Histone-mutant pediatric gliomas are a highly heterogeneous tumor entity. Different histone mutations correlate with different ages of onset, survival outcomes, brain regions, and partner alterations. We have developed models of histone-mutant gliomas that reflect this anatomic and genetic heterogeneity and provide evidence of subtype-specific biology and therapeutic targeting. See related commentary by Lubanszky and Hawkins, p. 1516. This article is highlighted in the In This Issue feature, p. 1501., (©2023 The Authors; Published by the American Association for Cancer Research.)

Published
2023
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27. Single substitution in H3.3G34 alters DNMT3A recruitment to cause progressive neurodegeneration.

Author

Khazaei S, Chen CCL, Andrade AF, Kabir N, Azarafshar P, Morcos SM, França JA, Lopes M, Lund PJ, Danieau G, Worme S, Adnani L, Nzirorera N, Chen X, Yogarajah G, Russo C, Zeinieh M, Wong CJ, Bryant L, Hébert S, Tong B, Sihota TS, Faury D, Puligandla E, Jawhar W, Sandy V, Cowan M, Nakada EM, Jerome-Majewska LA, Ellezam B, Gomes CC, Denecke J, Lessel D, McDonald MT, Pizoli CE, Taylor K, Cocanougher BT, Bhoj EJ, Gingras AC, Garcia BA, Lu C, Campos EI, Kleinman CL, Garzia L, and Jabado N

Subjects
Animals, Mice, DNA (Cytosine-5-)-Methyltransferases genetics, DNA Methylation genetics, DNA Modification Methylases genetics, Neuroinflammatory Diseases, DNA Methyltransferase 3A, Histones metabolism
Abstract

Germline histone H3.3 amino acid substitutions, including H3.3G34R/V, cause severe neurodevelopmental syndromes. To understand how these mutations impact brain development, we generated H3.3G34R/V/W knock-in mice and identified strikingly distinct developmental defects for each mutation. H3.3G34R-mutants exhibited progressive microcephaly and neurodegeneration, with abnormal accumulation of disease-associated microglia and concurrent neuronal depletion. G34R severely decreased H3K36me2 on the mutant H3.3 tail, impairing recruitment of DNA methyltransferase DNMT3A and its redistribution on chromatin. These changes were concurrent with sustained expression of complement and other innate immune genes possibly through loss of non-CG (CH) methylation and silencing of neuronal gene promoters through aberrant CG methylation. Complement expression in G34R brains may lead to neuroinflammation possibly accounting for progressive neurodegeneration. Our study reveals that H3.3G34-substitutions have differential impact on the epigenome, which underlie the diverse phenotypes observed, and uncovers potential roles for H3K36me2 and DNMT3A-dependent CH-methylation in modulating synaptic pruning and neuroinflammation in post-natal brains., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Published
2023
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28. Detection and genomic analysis of BRAF fusions in Juvenile Pilocytic Astrocytoma through the combination and integration of multi-omic data.

Author

Zwaig M, Baguette A, Hu B, Johnston M, Lakkis H, Nakada EM, Faury D, Juretic N, Ellezam B, Weil AG, Karamchandani J, Majewski J, Blanchette M, Taylor MD, Gallo M, Kleinman CL, Jabado N, and Ragoussis J

Subjects
Child, Adult, Humans, Multiomics, Proto-Oncogene Proteins B-raf genetics, Oncogene Proteins, Fusion genetics, Receptor-Like Protein Tyrosine Phosphatases, Class 5, Astrocytoma pathology, Brain Neoplasms pathology
Abstract

Background: Juvenile Pilocytic Astrocytomas (JPAs) are one of the most common pediatric brain tumors, and they are driven by aberrant activation of the mitogen-activated protein kinase (MAPK) signaling pathway. RAF-fusions are the most common genetic alterations identified in JPAs, with the prototypical KIAA1549-BRAF fusion leading to loss of BRAF's auto-inhibitory domain and subsequent constitutive kinase activation. JPAs are highly vascular and show pervasive immune infiltration, which can lead to low tumor cell purity in clinical samples. This can result in gene fusions that are difficult to detect with conventional omics approaches including RNA-Seq., Methods: To this effect, we applied RNA-Seq as well as linked-read whole-genome sequencing and in situ Hi-C as new approaches to detect and characterize low-frequency gene fusions at the genomic, transcriptomic and spatial level., Results: Integration of these datasets allowed the identification and detailed characterization of two novel BRAF fusion partners, PTPRZ1 and TOP2B, in addition to the canonical fusion with partner KIAA1549. Additionally, our Hi-C datasets enabled investigations of 3D genome architecture in JPAs which showed a high level of correlation in 3D compartment annotations between JPAs compared to other pediatric tumors, and high similarity to normal adult astrocytes. We detected interactions between BRAF and its fusion partners exclusively in tumor samples containing BRAF fusions., Conclusions: We demonstrate the power of integrating multi-omic datasets to identify low frequency fusions and characterize the JPA genome at high resolution. We suggest that linked-reads and Hi-C could be used in clinic for the detection and characterization of JPAs., (© 2022. The Author(s).)

Published
2022
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29. K27M in canonical and noncanonical H3 variants occurs in distinct oligodendroglial cell lineages in brain midline gliomas.

Author

Jessa S, Mohammadnia A, Harutyunyan AS, Hulswit M, Varadharajan S, Lakkis H, Kabir N, Bashardanesh Z, Hébert S, Faury D, Vladoiu MC, Worme S, Coutelier M, Krug B, Faria Andrade A, Pathania M, Bajic A, Weil AG, Ellezam B, Atkinson J, Dudley RWR, Farmer JP, Perreault S, Garcia BA, Larouche V, Blanchette M, Garzia L, Bhaduri A, Ligon KL, Bandopadhayay P, Taylor MD, Mack SC, Jabado N, and Kleinman CL

Subjects
Cell Lineage genetics, Brain, Epigenomics, Chromatin
Abstract

Canonical (H3.1/H3.2) and noncanonical (H3.3) histone 3 K27M-mutant gliomas have unique spatiotemporal distributions, partner alterations and molecular profiles. The contribution of the cell of origin to these differences has been challenging to uncouple from the oncogenic reprogramming induced by the mutation. Here, we perform an integrated analysis of 116 tumors, including single-cell transcriptome and chromatin accessibility, 3D chromatin architecture and epigenomic profiles, and show that K27M-mutant gliomas faithfully maintain chromatin configuration at developmental genes consistent with anatomically distinct oligodendrocyte precursor cells (OPCs). H3.3K27M thalamic gliomas map to prosomere 2-derived lineages. In turn, H3.1K27M ACVR1-mutant pontine gliomas uniformly mirror early ventral NKX6-1 + /SHH-dependent brainstem OPCs, whereas H3.3K27M gliomas frequently resemble dorsal PAX3 + /BMP-dependent progenitors. Our data suggest a context-specific vulnerability in H3.1K27M-mutant SHH-dependent ventral OPCs, which rely on acquisition of ACVR1 mutations to drive aberrant BMP signaling required for oncogenesis. The unifying action of K27M mutations is to restrict H3K27me3 at PRC2 landing sites, whereas other epigenetic changes are mainly contingent on the cell of origin chromatin state and cycling rate., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Published
2022
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30. Management of Inoperable Supra-Sellar Low-Grade Glioma With BRAF Mutation in Young Children.

Author

Howden K, Chapman S, Serletis D, Kazina C, Rafay MF, Faury D, Hazrati LN, Jabado N, and Vanan MI

Abstract

Pediatric low-grade gliomas (PLGGs) are the most common central nervous system (CNS) tumors in children. The current standard of care for surgically unresectable and/or progressive cases of PLGGs includes combination chemotherapy. PLGGs are molecularly characterized by alterations in the RAS/RAF/MAPK/ERK pathway in a majority of tumors. PLGGs harboring the BRAF-V600E mutation respond poorly to current chemotherapy strategies. We present a case of a two-year-old female with biopsy-proven low-grade glioma (LGG, pilocytic astrocytoma) involving the hypothalamic/optic chiasm region. At presentation, she had obstructive hydrocephalus, bitemporal hemianopia, central hypothyroidism, and right-sided hemiparesis due to the location/mass effect of the tumor. She was initially treated with chemotherapy (vincristine/carboplatin), but her tumor progressed at six weeks of treatment. She was subsequently started on dabrafenib as her tumor was positive for BRAF-V600E mutation. Dabrafenib monotherapy resulted in dramatic improvement in her clinical symptoms and near-complete resolution of tumor. Our experience and review of the literature suggest that LGGs with BRAF-V600E mutations may benefit from upfront targeted therapy in children. There is an urgent need for prospective clinical trials comparing the efficacy of upfront BRAF inhibitors versus standard chemotherapy in PLGGs with BRAF mutations., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Howden et al.)

Published
2021
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31. Histone H3.3G34-Mutant Interneuron Progenitors Co-opt PDGFRA for Gliomagenesis.

Author

Chen CCL, Deshmukh S, Jessa S, Hadjadj D, Lisi V, Andrade AF, Faury D, Jawhar W, Dali R, Suzuki H, Pathania M, A D, Dubois F, Woodward E, Hébert S, Coutelier M, Karamchandani J, Albrecht S, Brandner S, De Jay N, Gayden T, Bajic A, Harutyunyan AS, Marchione DM, Mikael LG, Juretic N, Zeinieh M, Russo C, Maestro N, Bassenden AV, Hauser P, Virga J, Bognar L, Klekner A, Zapotocky M, Vicha A, Krskova L, Vanova K, Zamecnik J, Sumerauer D, Ekert PG, Ziegler DS, Ellezam B, Filbin MG, Blanchette M, Hansford JR, Khuong-Quang DA, Berghuis AM, Weil AG, Garcia BA, Garzia L, Mack SC, Beroukhim R, Ligon KL, Taylor MD, Bandopadhayay P, Kramm C, Pfister SM, Korshunov A, Sturm D, Jones DTW, Salomoni P, Kleinman CL, and Jabado N

Subjects
Animals, Astrocytes metabolism, Astrocytes pathology, Brain Neoplasms pathology, Carcinogenesis pathology, Cell Lineage, Cellular Reprogramming genetics, Chromatin metabolism, Embryo, Mammalian metabolism, Epigenesis, Genetic, Gene Expression Regulation, Neoplastic, Gene Silencing, Glioma pathology, Histones metabolism, Lysine metabolism, Mice, Inbred C57BL, Models, Biological, Neoplasm Grading, Oligodendroglia metabolism, Promoter Regions, Genetic genetics, Prosencephalon embryology, Receptor, Platelet-Derived Growth Factor alpha metabolism, Transcription, Genetic, Transcriptome genetics, Brain Neoplasms genetics, Carcinogenesis genetics, Glioma genetics, Histones genetics, Interneurons metabolism, Mutation genetics, Neural Stem Cells metabolism, Receptor, Platelet-Derived Growth Factor alpha genetics
Abstract

Histone H3.3 glycine 34 to arginine/valine (G34R/V) mutations drive deadly gliomas and show exquisite regional and temporal specificity, suggesting a developmental context permissive to their effects. Here we show that 50% of G34R/V tumors (n = 95) bear activating PDGFRA mutations that display strong selection pressure at recurrence. Although considered gliomas, G34R/V tumors actually arise in GSX2/DLX-expressing interneuron progenitors, where G34R/V mutations impair neuronal differentiation. The lineage of origin may facilitate PDGFRA co-option through a chromatin loop connecting PDGFRA to GSX2 regulatory elements, promoting PDGFRA overexpression and mutation. At the single-cell level, G34R/V tumors harbor dual neuronal/astroglial identity and lack oligodendroglial programs, actively repressed by GSX2/DLX-mediated cell fate specification. G34R/V may become dispensable for tumor maintenance, whereas mutant-PDGFRA is potently oncogenic. Collectively, our results open novel research avenues in deadly tumors. G34R/V gliomas are neuronal malignancies where interneuron progenitors are stalled in differentiation by G34R/V mutations and malignant gliogenesis is promoted by co-option of a potentially targetable pathway, PDGFRA signaling., Competing Interests: Declaration of Interests P.B. and R.B. receive grant funding from the Novartis Institute of Biomedical Research for an unrelated project. J.R.H. has received compensation for consultation from Bayer for unrelated work., (Crown Copyright © 2020. Published by Elsevier Inc. All rights reserved.)

Published
2020
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32. H3.3 G34W Promotes Growth and Impedes Differentiation of Osteoblast-Like Mesenchymal Progenitors in Giant Cell Tumor of Bone.

Author

Khazaei S, De Jay N, Deshmukh S, Hendrikse LD, Jawhar W, Chen CCL, Mikael LG, Faury D, Marchione DM, Lanoix J, Bonneil É, Ishii T, Jain SU, Rossokhata K, Sihota TS, Eveleigh R, Lisi V, Harutyunyan AS, Jung S, Karamchandani J, Dickson BC, Turcotte R, Wunder JS, Thibault P, Lewis PW, Garcia BA, Mack SC, Taylor MD, Garzia L, Kleinman CL, and Jabado N

Subjects
Cell Differentiation, Humans, Bone Neoplasms genetics, Giant Cell Tumor of Bone genetics, Mesenchymal Stem Cells metabolism, Osteoblasts metabolism
Abstract

Glycine 34-to-tryptophan (G34W) substitutions in H3.3 arise in approximately 90% of giant cell tumor of bone (GCT). Here, we show H3.3 G34W is necessary for tumor formation. By profiling the epigenome, transcriptome, and secreted proteome of patient samples and tumor-derived cells CRISPR-Cas9-edited for H3.3 G34W, we show that H3.3K36me3 loss on mutant H3.3 alters the deposition of the repressive H3K27me3 mark from intergenic to genic regions, beyond areas of H3.3 deposition. This promotes redistribution of other chromatin marks and aberrant transcription, altering cell fate in mesenchymal progenitors and hindering differentiation. Single-cell transcriptomics reveals that H3.3 G34W stromal cells recapitulate a neoplastic trajectory from a SPP1 + osteoblast-like progenitor population toward an ACTA2 + myofibroblast-like population, which secretes extracellular matrix ligands predicted to recruit and activate osteoclasts. Our findings suggest that H3.3 G34W leads to GCT by sustaining a transformed state in osteoblast-like progenitors, which promotes neoplastic growth, pathologic recruitment of giant osteoclasts, and bone destruction. SIGNIFICANCE: This study shows that H3.3 G34W drives GCT tumorigenesis through aberrant epigenetic remodeling, altering differentiation trajectories in mesenchymal progenitors. H3.3 G34W promotes in neoplastic stromal cells an osteoblast-like progenitor state that enables undue interactions with the tumor microenvironment, driving GCT pathogenesis. These epigenetic changes may be amenable to therapeutic targeting in GCT. See related commentary by Licht, p. 1794 . This article is highlighted in the In This Issue feature, p. 1775 ., (©2020 American Association for Cancer Research.)

Published
2020
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33. Stalled developmental programs at the root of pediatric brain tumors.

Author

Jessa S, Blanchet-Cohen A, Krug B, Vladoiu M, Coutelier M, Faury D, Poreau B, De Jay N, Hébert S, Monlong J, Farmer WT, Donovan LK, Hu Y, McConechy MK, Cavalli FMG, Mikael LG, Ellezam B, Richer M, Allaire A, Weil AG, Atkinson J, Farmer JP, Dudley RWR, Larouche V, Crevier L, Albrecht S, Filbin MG, Sartelet H, Lutz PE, Nagy C, Turecki G, Costantino S, Dirks PB, Murai KK, Bourque G, Ragoussis J, Garzia L, Taylor MD, Jabado N, and Kleinman CL

Subjects
Animals, Brain pathology, Cell Line, Tumor, Humans, Infant, Medulloblastoma genetics, Medulloblastoma pathology, Mice, Neoplasms, Germ Cell and Embryonal genetics, Neoplasms, Germ Cell and Embryonal pathology, Nerve Fibers pathology, Nerve Fibers physiology, Prosencephalon cytology, Prosencephalon embryology, Rhabdoid Tumor genetics, Rhabdoid Tumor pathology, Single-Cell Analysis, Brain embryology, Brain Neoplasms genetics, Brain Neoplasms pathology, Gene Expression Regulation, Developmental
Abstract

Childhood brain tumors have suspected prenatal origins. To identify vulnerable developmental states, we generated a single-cell transcriptome atlas of >65,000 cells from embryonal pons and forebrain, two major tumor locations. We derived signatures for 191 distinct cell populations and defined the regional cellular diversity and differentiation dynamics. Projection of bulk tumor transcriptomes onto this dataset shows that WNT medulloblastomas match the rhombic lip-derived mossy fiber neuronal lineage and embryonal tumors with multilayered rosettes fully recapitulate a neuronal lineage, while group 2a/b atypical teratoid/rhabdoid tumors may originate outside the neuroectoderm. Importantly, single-cell tumor profiles reveal highly defined cell hierarchies that mirror transcriptional programs of the corresponding normal lineages. Our findings identify impaired differentiation of specific neural progenitors as a common mechanism underlying these pediatric cancers and provide a rational framework for future modeling and therapeutic interventions.

Published
2019
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35. H3K27M induces defective chromatin spread of PRC2-mediated repressive H3K27me2/me3 and is essential for glioma tumorigenesis.

Author

Harutyunyan AS, Krug B, Chen H, Papillon-Cavanagh S, Zeinieh M, De Jay N, Deshmukh S, Chen CCL, Belle J, Mikael LG, Marchione DM, Li R, Nikbakht H, Hu B, Cagnone G, Cheung WA, Mohammadnia A, Bechet D, Faury D, McConechy MK, Pathania M, Jain SU, Ellezam B, Weil AG, Montpetit A, Salomoni P, Pastinen T, Lu C, Lewis PW, Garcia BA, Kleinman CL, Jabado N, and Majewski J

Subjects
Adolescent, Aged, Animals, Brain Neoplasms pathology, CRISPR-Cas Systems, Carcinogenesis genetics, Cell Line, Tumor, Cell Proliferation genetics, Child, CpG Islands genetics, DNA Methylation genetics, Epigenesis, Genetic, Female, Gene Editing methods, Gene Expression Regulation, Neoplastic, Glioblastoma pathology, HEK293 Cells, Histone Code genetics, Histones metabolism, Humans, Lysine genetics, Male, Methionine genetics, Mice, Mice, Inbred NOD, Mice, SCID, Mutation, Neurogenesis genetics, Xenograft Model Antitumor Assays, Brain Neoplasms genetics, Chromatin metabolism, Glioblastoma genetics, Histones genetics, Polycomb Repressive Complex 2 metabolism
Abstract

Lys-27-Met mutations in histone 3 genes (H3K27M) characterize a subgroup of deadly gliomas and decrease genome-wide H3K27 trimethylation. Here we use primary H3K27M tumor lines and isogenic CRISPR-edited controls to assess H3K27M effects in vitro and in vivo. We find that whereas H3K27me3 and H3K27me2 are normally deposited by PRC2 across broad regions, their deposition is severely reduced in H3.3K27M cells. H3K27me3 is unable to spread from large unmethylated CpG islands, while H3K27me2 can be deposited outside these PRC2 high-affinity sites but to levels corresponding to H3K27me3 deposition in wild-type cells. Our findings indicate that PRC2 recruitment and propagation on chromatin are seemingly unaffected by K27M, which mostly impairs spread of the repressive marks it catalyzes, especially H3K27me3. Genome-wide loss of H3K27me3 and me2 deposition has limited transcriptomic consequences, preferentially affecting lowly-expressed genes regulating neurogenesis. Removal of H3K27M restores H3K27me2/me3 spread, impairs cell proliferation, and completely abolishes their capacity to form tumors in mice.

Published
2019
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36. Germline and somatic FGFR1 abnormalities in dysembryoplastic neuroepithelial tumors.

Author

Rivera B, Gayden T, Carrot-Zhang J, Nadaf J, Boshari T, Faury D, Zeinieh M, Blanc R, Burk DL, Fahiminiya S, Bareke E, Schüller U, Monoranu CM, Sträter R, Kerl K, Niederstadt T, Kurlemann G, Ellezam B, Michalak Z, Thom M, Lockhart PJ, Leventer RJ, Ohm M, MacGregor D, Jones D, Karamchandani J, Greenwood CM, Berghuis AM, Bens S, Siebert R, Zakrzewska M, Liberski PP, Zakrzewski K, Sisodiya SM, Paulus W, Albrecht S, Hasselblatt M, Jabado N, Foulkes WD, and Majewski J

Subjects
Adolescent, Adult, Female, HEK293 Cells, Humans, MAP Kinase Signaling System physiology, Male, Proto-Oncogene Proteins B-raf genetics, Young Adult, Brain Neoplasms genetics, DNA Copy Number Variations genetics, Glioma genetics, Mutation genetics, Receptor, Fibroblast Growth Factor, Type 1 genetics
Abstract

Dysembryoplastic neuroepithelial tumor (DNET) is a benign brain tumor associated with intractable drug-resistant epilepsy. In order to identify underlying genetic alterations and molecular mechanisms, we examined three family members affected by multinodular DNETs as well as 100 sporadic tumors from 96 patients, which had been referred to us as DNETs. We performed whole-exome sequencing on 46 tumors and targeted sequencing for hotspot FGFR1 mutations and BRAF p.V600E was used on the remaining samples. FISH, copy number variation assays and Sanger sequencing were used to validate the findings. By whole-exome sequencing of the familial cases, we identified a novel germline FGFR1 mutation, p.R661P. Somatic activating FGFR1 mutations (p.N546K or p.K656E) were observed in the tumor samples and further evidence for functional relevance was obtained by in silico modeling. The FGFR1 p.K656E mutation was confirmed to be in cis with the germline p.R661P variant. In 43 sporadic cases, in which the diagnosis of DNET could be confirmed on central blinded neuropathology review, FGFR1 alterations were also frequent and mainly comprised intragenic tyrosine kinase FGFR1 duplication and multiple mutants in cis (25/43; 58.1 %) while BRAF p.V600E alterations were absent (0/43). In contrast, in 53 cases, in which the diagnosis of DNET was not confirmed, FGFR1 alterations were less common (10/53; 19 %; p < 0.0001) and hotspot BRAF p.V600E (12/53; 22.6 %) (p < 0.001) prevailed. We observed overexpression of phospho-ERK in FGFR1 p.R661P and p.N546K mutant expressing HEK293 cells as well as FGFR1 mutated tumor samples, supporting enhanced MAP kinase pathway activation under these conditions. In conclusion, constitutional and somatic FGFR1 alterations and MAP kinase pathway activation are key events in the pathogenesis of DNET. These findings point the way towards existing targeted therapies.

Published
2016
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37. Spatial and temporal homogeneity of driver mutations in diffuse intrinsic pontine glioma.

Author

Nikbakht H, Panditharatna E, Mikael LG, Li R, Gayden T, Osmond M, Ho CY, Kambhampati M, Hwang EI, Faury D, Siu A, Papillon-Cavanagh S, Bechet D, Ligon KL, Ellezam B, Ingram WJ, Stinson C, Moore AS, Warren KE, Karamchandani J, Packer RJ, Jabado N, Majewski J, and Nazarian J

Subjects
Activin Receptors, Type I genetics, Activin Receptors, Type I metabolism, Autopsy, Brain Mapping, Brain Stem metabolism, Brain Stem pathology, Brain Stem Neoplasms metabolism, Brain Stem Neoplasms pathology, Carcinogenesis metabolism, Carcinogenesis pathology, Cerebrum metabolism, Cerebrum pathology, Child, Class Ia Phosphatidylinositol 3-Kinase, Clonal Evolution, Glioma metabolism, Glioma pathology, Histones metabolism, Humans, Phosphatidylinositol 3-Kinases genetics, Phosphatidylinositol 3-Kinases metabolism, Phosphoprotein Phosphatases genetics, Phosphoprotein Phosphatases metabolism, Protein Phosphatase 2C, Signal Transduction, Stereotaxic Techniques, Time Factors, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Protein p53 metabolism, Brain Stem Neoplasms genetics, Carcinogenesis genetics, Gene Expression Regulation, Neoplastic, Glioma genetics, Histones genetics, Mutation
Abstract

Diffuse Intrinsic Pontine Gliomas (DIPGs) are deadly paediatric brain tumours where needle biopsies help guide diagnosis and targeted therapies. To address spatial heterogeneity, here we analyse 134 specimens from various neuroanatomical structures of whole autopsy brains from nine DIPG patients. Evolutionary reconstruction indicates histone 3 (H3) K27M--including H3.2K27M--mutations potentially arise first and are invariably associated with specific, high-fidelity obligate partners throughout the tumour and its spread, from diagnosis to end-stage disease, suggesting mutual need for tumorigenesis. These H3K27M ubiquitously-associated mutations involve alterations in TP53 cell-cycle (TP53/PPM1D) or specific growth factor pathways (ACVR1/PIK3R1). Later oncogenic alterations arise in sub-clones and often affect the PI3K pathway. Our findings are consistent with early tumour spread outside the brainstem including the cerebrum. The spatial and temporal homogeneity of main driver mutations in DIPG implies they will be captured by limited biopsies and emphasizes the need to develop therapies specifically targeting obligate oncohistone partnerships.

Published
2016
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38. Non-random aneuploidy specifies subgroups of pilocytic astrocytoma and correlates with older age.

Author

Fontebasso AM, Shirinian M, Khuong-Quang DA, Bechet D, Gayden T, Kool M, De Jay N, Jacob K, Gerges N, Hutter B, Şeker-Cin H, Witt H, Montpetit A, Brunet S, Lepage P, Bourret G, Klekner A, Bognár L, Hauser P, Garami M, Farmer JP, Montes JL, Atkinson J, Lambert S, Kwan T, Korshunov A, Tabori U, Collins VP, Albrecht S, Faury D, Pfister SM, Paulus W, Hasselblatt M, Jones DT, and Jabado N

Subjects
Adult, Age Factors, Astrocytoma genetics, Astrocytoma pathology, Brain Neoplasms genetics, Brain Neoplasms pathology, Child, Cohort Studies, Female, Gene Expression Profiling, Humans, Male, Mutation genetics, Neoplasm Staging, Prognosis, Proto-Oncogene Proteins B-raf genetics, Proto-Oncogene Proteins c-mdm2 genetics, RNA, Messenger genetics, Real-Time Polymerase Chain Reaction, Receptor, Fibroblast Growth Factor, Type 1 genetics, Reverse Transcriptase Polymerase Chain Reaction, Young Adult, Aneuploidy, Astrocytoma classification, Biomarkers, Tumor genetics, Brain Neoplasms classification
Abstract

Pilocytic astrocytoma (PA) is the most common brain tumor in children but is rare in adults, and hence poorly studied in this age group. We investigated 222 PA and report increased aneuploidy in older patients. Aneuploid genomes were identified in 45% of adult compared with 17% of pediatric PA. Gains were non-random, favoring chromosomes 5, 7, 6 and 11 in order of frequency, and preferentially affecting non-cerebellar PA and tumors with BRAF V600E mutations and not with KIAA1549-BRAF fusions or FGFR1 mutations. Aneuploid PA differentially expressed genes involved in CNS development, the unfolded protein response, and regulators of genomic stability and the cell cycle (MDM2, PLK2),whose correlated programs were overexpressed specifically in aneuploid PA compared to other glial tumors. Thus, convergence of pathways affecting the cell cycle and genomic stability may favor aneuploidy in PA, possibly representing an additional molecular driver in older patients with this brain tumor.

Published
2015
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39. Specific detection of methionine 27 mutation in histone 3 variants (H3K27M) in fixed tissue from high-grade astrocytomas.

Author

Bechet D, Gielen GG, Korshunov A, Pfister SM, Rousso C, Faury D, Fiset PO, Benlimane N, Lewis PW, Lu C, David Allis C, Kieran MW, Ligon KL, Pietsch T, Ellezam B, Albrecht S, and Jabado N

Subjects
Adolescent, Astrocytoma pathology, Brain metabolism, Brain pathology, Brain Neoplasms pathology, Child, Cohort Studies, DNA Mutational Analysis, Female, Genotype, Humans, Male, Astrocytoma genetics, Brain Neoplasms genetics, Histones genetics, Methionine genetics, Mutation genetics
Abstract

Studies in pediatric high-grade astrocytomas (HGA) by our group and others have uncovered recurrent somatic mutations affecting highly conserved residues in histone 3 (H3) variants. One of these mutations leads to analogous p.Lys27Met (K27M) mutations in both H3.3 and H3.1 variants, is associated with rapid fatal outcome, and occurs specifically in HGA of the midline in children and young adults. This includes diffuse intrinsic pontine gliomas (80 %) and thalamic or spinal HGA (>90 %), which are surgically challenging locations with often limited tumor material available and critical need for specific histopathological markers. Here, we analyzed formalin-fixed paraffin-embedded tissues from 143 pediatric HGA and 297 other primary brain tumors or normal brain. Immunohistochemical staining for H3K27M was compared to tumor genotype, and also compared to H3 tri-methylated lysine 27 (H3K27me3) staining, previously shown to be drastically decreased in samples carrying this mutation. There was a 100 % concordance between genotype and immunohistochemical analysis of H3K27M in tumor samples. Mutant H3K27M was expressed in the majority of tumor cells, indicating limited intra-tumor heterogeneity for this specific mutation within the limits of our dataset. Both H3.1 and H3.3K27M mutants were recognized by this antibody while non-neoplastic elements, such as endothelial and vascular smooth muscle cells or lymphocytes, did not stain. H3K27me3 immunoreactivity was largely mutually exclusive with H3K27M positivity. These results demonstrate that mutant H3K27M can be specifically identified with high specificity and sensitivity using an H3K27M antibody and immunohistochemistry. Use of this antibody in the clinical setting will prove very useful for diagnosis, especially in the context of small biopsies in challenging midline tumors and will help orient care in the context of the extremely poor prognosis associated with this mutation.

Published
2014
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40. Recurrent somatic mutations in ACVR1 in pediatric midline high-grade astrocytoma.

Author

Fontebasso AM, Papillon-Cavanagh S, Schwartzentruber J, Nikbakht H, Gerges N, Fiset PO, Bechet D, Faury D, De Jay N, Ramkissoon LA, Corcoran A, Jones DT, Sturm D, Johann P, Tomita T, Goldman S, Nagib M, Bendel A, Goumnerova L, Bowers DC, Leonard JR, Rubin JB, Alden T, Browd S, Geyer JR, Leary S, Jallo G, Cohen K, Gupta N, Prados MD, Carret AS, Ellezam B, Crevier L, Klekner A, Bognar L, Hauser P, Garami M, Myseros J, Dong Z, Siegel PM, Malkin H, Ligon AH, Albrecht S, Pfister SM, Ligon KL, Majewski J, Jabado N, and Kieran MW

Subjects
Animals, Base Sequence, Bone Morphogenetic Proteins metabolism, Child, DNA Copy Number Variations genetics, DNA Methylation genetics, Humans, Immunohistochemistry, In Situ Hybridization, Fluorescence, Molecular Sequence Data, Sequence Analysis, DNA, Smad Proteins metabolism, Activin Receptors, Type I genetics, Astrocytoma genetics, Brain Neoplasms genetics, Gene Expression Regulation, Neoplastic genetics, Genome, Human genetics, Mutation genetics
Abstract

Pediatric midline high-grade astrocytomas (mHGAs) are incurable with few treatment targets identified. Most tumors harbor mutations encoding p.Lys27Met in histone H3 variants. In 40 treatment-naive mHGAs, 39 analyzed by whole-exome sequencing, we find additional somatic mutations specific to tumor location. Gain-of-function mutations in ACVR1 occur in tumors of the pons in conjunction with histone H3.1 p.Lys27Met substitution, whereas FGFR1 mutations or fusions occur in thalamic tumors associated with histone H3.3 p.Lys27Met substitution. Hyperactivation of the bone morphogenetic protein (BMP)-ACVR1 developmental pathway in mHGAs harboring ACVR1 mutations led to increased levels of phosphorylated SMAD1, SMAD5 and SMAD8 and upregulation of BMP downstream early-response genes in tumor cells. Global DNA methylation profiles were significantly associated with the p.Lys27Met alteration, regardless of the mutant histone H3 variant and irrespective of tumor location, supporting the role of this substitution in driving the epigenetic phenotype. This work considerably expands the number of potential treatment targets and further justifies pretreatment biopsy in pediatric mHGA as a means to orient therapeutic efforts in this disease.

Published
2014
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41. Fusion of TTYH1 with the C19MC microRNA cluster drives expression of a brain-specific DNMT3B isoform in the embryonal brain tumor ETMR.

Author

Kleinman CL, Gerges N, Papillon-Cavanagh S, Sin-Chan P, Pramatarova A, Quang DA, Adoue V, Busche S, Caron M, Djambazian H, Bemmo A, Fontebasso AM, Spence T, Schwartzentruber J, Albrecht S, Hauser P, Garami M, Klekner A, Bognar L, Montes JL, Staffa A, Montpetit A, Berube P, Zakrzewska M, Zakrzewski K, Liberski PP, Dong Z, Siegel PM, Duchaine T, Perotti C, Fleming A, Faury D, Remke M, Gallo M, Dirks P, Taylor MD, Sladek R, Pastinen T, Chan JA, Huang A, Majewski J, and Jabado N

Subjects
Child, Preschool, DNA (Cytosine-5-)-Methyltransferases metabolism, DNA Methylation, Gene Expression Regulation, Neoplastic, Gene Fusion, Humans, Male, Protein Isoforms, Retinoblastoma-Like Protein p130 genetics, Xenograft Model Antitumor Assays, DNA Methyltransferase 3B, Brain Neoplasms genetics, Chromosomes, Human, Pair 19, DNA (Cytosine-5-)-Methyltransferases genetics, Membrane Proteins genetics, MicroRNAs genetics, Neoplasms, Germ Cell and Embryonal genetics
Abstract

Embryonal tumors with multilayered rosettes (ETMRs) are rare, deadly pediatric brain tumors characterized by high-level amplification of the microRNA cluster C19MC. We performed integrated genetic and epigenetic analyses of 12 ETMR samples and identified, in all cases, C19MC fusions to TTYH1 driving expression of the microRNAs. ETMR tumors, cell lines and xenografts showed a specific DNA methylation pattern distinct from those of other tumors and normal tissues. We detected extreme overexpression of a previously uncharacterized isoform of DNMT3B originating at an alternative promoter that is active only in the first weeks of neural tube development. Transcriptional and immunohistochemical analyses suggest that C19MC-dependent DNMT3B deregulation is mediated by RBL2, a known repressor of DNMT3B. Transfection with individual C19MC microRNAs resulted in DNMT3B upregulation and RBL2 downregulation in cultured cells. Our data suggest a potential oncogenic re-engagement of an early developmental program in ETMR via epigenetic alteration mediated by an embryonic, brain-specific DNMT3B isoform.

Published
2014
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42. Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma.

Author

Jones DT, Hutter B, Jäger N, Korshunov A, Kool M, Warnatz HJ, Zichner T, Lambert SR, Ryzhova M, Quang DA, Fontebasso AM, Stütz AM, Hutter S, Zuckermann M, Sturm D, Gronych J, Lasitschka B, Schmidt S, Seker-Cin H, Witt H, Sultan M, Ralser M, Northcott PA, Hovestadt V, Bender S, Pfaff E, Stark S, Faury D, Schwartzentruber J, Majewski J, Weber UD, Zapatka M, Raeder B, Schlesner M, Worth CL, Bartholomae CC, von Kalle C, Imbusch CD, Radomski S, Lawerenz C, van Sluis P, Koster J, Volckmann R, Versteeg R, Lehrach H, Monoranu C, Winkler B, Unterberg A, Herold-Mende C, Milde T, Kulozik AE, Ebinger M, Schuhmann MU, Cho YJ, Pomeroy SL, von Deimling A, Witt O, Taylor MD, Wolf S, Karajannis MA, Eberhart CG, Scheurlen W, Hasselblatt M, Ligon KL, Kieran MW, Korbel JO, Yaspo ML, Brors B, Felsberg J, Reifenberger G, Collins VP, Jabado N, Eils R, Lichter P, and Pfister SM

Subjects
Animals, Astrocytoma metabolism, Base Sequence, Brain Neoplasms metabolism, Cell Line, Cell Transformation, Neoplastic genetics, Cell Transformation, Neoplastic metabolism, Chromosome Breakpoints, Chromosomes, Human, Pair 6, Chromosomes, Human, Pair 9, Fibroblast Growth Factors metabolism, Humans, MAP Kinase Signaling System, Mice, Models, Molecular, Oncogene Proteins, Fusion chemistry, Oncogene Proteins, Fusion genetics, Protein Conformation, Proto-Oncogene Proteins B-raf chemistry, Proto-Oncogene Proteins B-raf genetics, Receptor, Fibroblast Growth Factor, Type 1 metabolism, Receptor, trkB metabolism, Astrocytoma genetics, Brain Neoplasms genetics, Mutation, Receptor, Fibroblast Growth Factor, Type 1 genetics, Receptor, trkB genetics
Abstract

Pilocytic astrocytoma, the most common childhood brain tumor, is typically associated with mitogen-activated protein kinase (MAPK) pathway alterations. Surgically inaccessible midline tumors are therapeutically challenging, showing sustained tendency for progression and often becoming a chronic disease with substantial morbidities. Here we describe whole-genome sequencing of 96 pilocytic astrocytomas, with matched RNA sequencing (n = 73), conducted by the International Cancer Genome Consortium (ICGC) PedBrain Tumor Project. We identified recurrent activating mutations in FGFR1 and PTPN11 and new NTRK2 fusion genes in non-cerebellar tumors. New BRAF-activating changes were also observed. MAPK pathway alterations affected all tumors analyzed, with no other significant mutations identified, indicating that pilocytic astrocytoma is predominantly a single-pathway disease. Notably, we identified the same FGFR1 mutations in a subset of H3F3A-mutated pediatric glioblastoma with additional alterations in the NF1 gene. Our findings thus identify new potential therapeutic targets in distinct subsets of pilocytic astrocytoma and childhood glioblastoma.

Published
2013
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43. Pediatric high-grade astrocytomas: a distinct neuro-oncological paradigm.

Author

Gerges N, Fontebasso AM, Albrecht S, Faury D, and Jabado N

Abstract

Brain tumors are the leading cause of cancer-related death in children. High-grade astrocytomas (HGAs), in particular, are lethal in children across all ages. Integrative genome-wide analyses of the tumor's genome, transcriptome and epigenome, using next-generation sequencing technologies and genome-wide DNA methylation arrays, have provided valuable breakthroughs in our understanding of the pathogenesis of HGAs across all ages. Recent profiling studies have provided insight into the epigenetic nature of gliomas in young adults and HGAs in children, particularly with the identification of recurrent gain-of-function driver mutations in the isocitrate dehydrogenase 1 and 2 genes (IDH1/2) and the epigenetic influence of their oncometabolite 2-hydroxyglutarate, as well as mutations in the histone 3 variant 3 gene (H3F3A) and loss-of-function mutations in the histone 3 lysine 36 trimethyltransferase gene (SETD2). Mutations in H3F3A result in amino acid substitutions at residues thought to directly (K27M) or indirectly (G34R/V) affect histone post-translational modifications, suggesting they have the capacity to affect the epigenome in a profound manner. Here, we review recent genomic studies, and discuss evidence supporting the molecular characterization of pediatric HGAs to complement traditional approaches, such as histology of resected tumors. We also describe newly identified molecular mechanisms and discuss putative therapeutic approaches for HGAs specific to pediatrics, highlighting the necessity for the evolution of HGA disease management approaches.

Published
2013
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44. Mutations in SETD2 and genes affecting histone H3K36 methylation target hemispheric high-grade gliomas.

Author

Fontebasso AM, Schwartzentruber J, Khuong-Quang DA, Liu XY, Sturm D, Korshunov A, Jones DT, Witt H, Kool M, Albrecht S, Fleming A, Hadjadj D, Busche S, Lepage P, Montpetit A, Staffa A, Gerges N, Zakrzewska M, Zakrzewski K, Liberski PP, Hauser P, Garami M, Klekner A, Bognar L, Zadeh G, Faury D, Pfister SM, Jabado N, and Majewski J

Subjects
Adolescent, Adult, Age Factors, Brain Neoplasms metabolism, Brain Neoplasms pathology, Case-Control Studies, Child, Cohort Studies, Exome, Glioma metabolism, Glioma pathology, Histone Methyltransferases, Humans, Infant, Methylation, Middle Aged, Neoplasm Grading, Young Adult, Brain Neoplasms genetics, Glioma genetics, Histone-Lysine N-Methyltransferase genetics, Histone-Lysine N-Methyltransferase metabolism, Histones metabolism, Mutation genetics
Abstract

Recurrent mutations affecting the histone H3.3 residues Lys27 or indirectly Lys36 are frequent drivers of pediatric high-grade gliomas (over 30% of HGGs). To identify additional driver mutations in HGGs, we investigated a cohort of 60 pediatric HGGs using whole-exome sequencing (WES) and compared them to 543 exomes from non-cancer control samples. We identified mutations in SETD2, a H3K36 trimethyltransferase, in 15% of pediatric HGGs, a result that was genome-wide significant (FDR = 0.029). Most SETD2 alterations were truncating mutations. Sequencing the gene in this cohort and another validation cohort (123 gliomas from all ages and grades) showed SETD2 mutations to be specific to high-grade tumors affecting 15% of pediatric HGGs (11/73) and 8% of adult HGGs (5/65) while no SETD2 mutations were identified in low-grade diffuse gliomas (0/45). Furthermore, SETD2 mutations were mutually exclusive with H3F3A mutations in HGGs (P = 0.0492) while they partly overlapped with IDH1 mutations (4/14), and SETD2-mutant tumors were found exclusively in the cerebral hemispheres (P = 0.0055). SETD2 is the only H3K36 trimethyltransferase in humans, and SETD2-mutant tumors showed a substantial decrease in H3K36me3 levels (P < 0.001), indicating that the mutations are loss-of-function. These data suggest that loss-of-function SETD2 mutations occur in older children and young adults and are specific to HGG of the cerebral cortex, similar to the H3.3 G34R/V and IDH mutations. Taken together, our results suggest that mutations disrupting the histone code at H3K36, including H3.3 G34R/V, IDH1 and/or SETD2 mutations, are central to the genesis of hemispheric HGGs in older children and young adults.

Published
2013
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45. Frequent ATRX mutations and loss of expression in adult diffuse astrocytic tumors carrying IDH1/IDH2 and TP53 mutations.

Author

Liu XY, Gerges N, Korshunov A, Sabha N, Khuong-Quang DA, Fontebasso AM, Fleming A, Hadjadj D, Schwartzentruber J, Majewski J, Dong Z, Siegel P, Albrecht S, Croul S, Jones DT, Kool M, Tonjes M, Reifenberger G, Faury D, Zadeh G, Pfister S, and Jabado N

Subjects
Adult, Aged, Astrocytoma classification, Astrocytoma pathology, Brain Neoplasms classification, Brain Neoplasms pathology, Female, Humans, Isocitrate Dehydrogenase genetics, Male, Middle Aged, Mutation Rate, RNA, Messenger metabolism, X-linked Nuclear Protein, Young Adult, Astrocytoma genetics, Brain Neoplasms genetics, DNA Helicases genetics, Gene Expression Regulation, Neoplastic genetics, Mutation genetics, Nuclear Proteins genetics, Tumor Suppressor Protein p53 genetics
Abstract

Gliomas are the most common primary brain tumors in children and adults. We recently identified frequent alterations in chromatin remodelling pathways including recurrent mutations in H3F3A and mutations in ATRX (α-thalassemia/mental-retardation-syndrome-X-linked) in pediatric and young adult glioblastoma (GBM, WHO grade IV astrocytoma). H3F3A mutations were specific to pediatric high-grade gliomas and identified in only 3.4 % of adult GBM. Using sequencing and/or immunohistochemical analyses, we investigated ATRX alterations (mutation/loss of expression) and their association with TP53 and IDH1 or IDH2 mutations in 140 adult WHO grade II, III and IV gliomas, 17 pediatric WHO grade II and III astrocytomas and 34 pilocytic astrocytomas. In adults, ATRX aberrations were detected in 33 % of grade II and 46 % of grade III gliomas, as well as in 80 % of secondary and 7 % of primary GBMs. They were absent in the 17 grade II and III astrocytomas in children, and the 34 pilocytic astrocytomas. ATRX alterations closely overlapped with mutations in IDH1/2 (p < 0.0001) and TP53 (p < 0.0001) in samples across all WHO grades. They were prevalent in astrocytomas and oligoastrocytomas, but were absent in oligodendrogliomas (p < 0.0001). No significant association of ATRX mutation/loss of expression and alternative lengthening of telomeres was identified in our cohort. In summary, our data show that ATRX alterations are frequent in adult diffuse gliomas and are specific to astrocytic tumors carrying IDH1/2 and TP53 mutations. Combined alteration of these genes may contribute to drive the neoplastic growth in a major subset of diffuse astrocytomas in adults.

Published
2012
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46. Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma.

Author

Sturm D, Witt H, Hovestadt V, Khuong-Quang DA, Jones DT, Konermann C, Pfaff E, Tönjes M, Sill M, Bender S, Kool M, Zapatka M, Becker N, Zucknick M, Hielscher T, Liu XY, Fontebasso AM, Ryzhova M, Albrecht S, Jacob K, Wolter M, Ebinger M, Schuhmann MU, van Meter T, Frühwald MC, Hauch H, Pekrun A, Radlwimmer B, Niehues T, von Komorowski G, Dürken M, Kulozik AE, Madden J, Donson A, Foreman NK, Drissi R, Fouladi M, Scheurlen W, von Deimling A, Monoranu C, Roggendorf W, Herold-Mende C, Unterberg A, Kramm CM, Felsberg J, Hartmann C, Wiestler B, Wick W, Milde T, Witt O, Lindroth AM, Schwartzentruber J, Faury D, Fleming A, Zakrzewska M, Liberski PP, Zakrzewski K, Hauser P, Garami M, Klekner A, Bognar L, Morrissy S, Cavalli F, Taylor MD, van Sluis P, Koster J, Versteeg R, Volckmann R, Mikkelsen T, Aldape K, Reifenberger G, Collins VP, Majewski J, Korshunov A, Lichter P, Plass C, Jabado N, and Pfister SM

Subjects
Adult, Brain Neoplasms pathology, Child, DNA Methylation, Glioblastoma pathology, Humans, Receptor, Platelet-Derived Growth Factor alpha genetics, Transcriptome, Brain Neoplasms genetics, Epigenesis, Genetic, Glioblastoma genetics, Histones genetics, Isocitrate Dehydrogenase genetics, Mutation
Abstract

Glioblastoma (GBM) is a brain tumor that carries a dismal prognosis and displays considerable heterogeneity. We have recently identified recurrent H3F3A mutations affecting two critical amino acids (K27 and G34) of histone H3.3 in one-third of pediatric GBM. Here, we show that each H3F3A mutation defines an epigenetic subgroup of GBM with a distinct global methylation pattern, and that they are mutually exclusive with IDH1 mutations, which characterize a third mutation-defined subgroup. Three further epigenetic subgroups were enriched for hallmark genetic events of adult GBM and/or established transcriptomic signatures. We also demonstrate that the two H3F3A mutations give rise to GBMs in separate anatomic compartments, with differential regulation of transcription factors OLIG1, OLIG2, and FOXG1, possibly reflecting different cellular origins., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Published
2012
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47. K27M mutation in histone H3.3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas.

Author

Khuong-Quang DA, Buczkowicz P, Rakopoulos P, Liu XY, Fontebasso AM, Bouffet E, Bartels U, Albrecht S, Schwartzentruber J, Letourneau L, Bourgey M, Bourque G, Montpetit A, Bourret G, Lepage P, Fleming A, Lichter P, Kool M, von Deimling A, Sturm D, Korshunov A, Faury D, Jones DT, Majewski J, Pfister SM, Jabado N, and Hawkins C

Subjects
Adolescent, Brain Stem Neoplasms mortality, Brain Stem Neoplasms pathology, Child, Child, Preschool, Female, Gene Expression Profiling, Glioma mortality, Glioma pathology, Humans, Infant, Male, Mutation, Prognosis, Survival Rate, Brain Stem Neoplasms genetics, Glioma genetics, Histones genetics, Pons pathology
Abstract

Pediatric glioblastomas (GBM) including diffuse intrinsic pontine gliomas (DIPG) are devastating brain tumors with no effective therapy. Here, we investigated clinical and biological impacts of histone H3.3 mutations. Forty-two DIPGs were tested for H3.3 mutations. Wild-type versus mutated (K27M-H3.3) subgroups were compared for HIST1H3B, IDH, ATRX and TP53 mutations, copy number alterations and clinical outcome. K27M-H3.3 occurred in 71 %, TP53 mutations in 77 % and ATRX mutations in 9 % of DIPGs. ATRX mutations were more frequent in older children (p < 0.0001). No G34V/R-H3.3, IDH1/2 or H3.1 mutations were identified. K27M-H3.3 DIPGs showed specific copy number changes, including all gains/amplifications of PDGFRA and MYC/PVT1 loci. Notably, all long-term survivors were H3.3 wild type and this group of patients had better overall survival. K27M-H3.3 mutation defines clinically and biologically distinct subgroups and is prevalent in DIPG, which will impact future therapeutic trial design. K27M- and G34V-H3.3 have location-based incidence (brainstem/cortex) and potentially play distinct roles in pediatric GBM pathogenesis. K27M-H3.3 is universally associated with short survival in DIPG, while patients wild-type for H3.3 show improved survival. Based on prognostic and therapeutic implications, our findings argue for H3.3-mutation testing at diagnosis, which should be rapidly integrated into the clinical decision-making algorithm, particularly in atypical DIPG.

Published
2012
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48. Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma.

Author

Schwartzentruber J, Korshunov A, Liu XY, Jones DT, Pfaff E, Jacob K, Sturm D, Fontebasso AM, Quang DA, Tönjes M, Hovestadt V, Albrecht S, Kool M, Nantel A, Konermann C, Lindroth A, Jäger N, Rausch T, Ryzhova M, Korbel JO, Hielscher T, Hauser P, Garami M, Klekner A, Bognar L, Ebinger M, Schuhmann MU, Scheurlen W, Pekrun A, Frühwald MC, Roggendorf W, Kramm C, Dürken M, Atkinson J, Lepage P, Montpetit A, Zakrzewska M, Zakrzewski K, Liberski PP, Dong Z, Siegel P, Kulozik AE, Zapatka M, Guha A, Malkin D, Felsberg J, Reifenberger G, von Deimling A, Ichimura K, Collins VP, Witt H, Milde T, Witt O, Zhang C, Castelo-Branco P, Lichter P, Faury D, Tabori U, Plass C, Majewski J, Pfister SM, and Jabado N

Subjects
Adaptor Proteins, Signal Transducing genetics, Base Sequence, Child, Chromatin metabolism, Co-Repressor Proteins, DNA Helicases genetics, DNA Mutational Analysis, Exome genetics, Gene Expression Profiling, Histones metabolism, Humans, Molecular Chaperones, Molecular Sequence Data, Nuclear Proteins genetics, Telomere genetics, Tumor Suppressor Protein p53 genetics, X-linked Nuclear Protein, Chromatin genetics, Chromatin Assembly and Disassembly genetics, Glioblastoma genetics, Histones genetics, Mutation genetics
Abstract

Glioblastoma multiforme (GBM) is a lethal brain tumour in adults and children. However, DNA copy number and gene expression signatures indicate differences between adult and paediatric cases. To explore the genetic events underlying this distinction, we sequenced the exomes of 48 paediatric GBM samples. Somatic mutations in the H3.3-ATRX-DAXX chromatin remodelling pathway were identified in 44% of tumours (21/48). Recurrent mutations in H3F3A, which encodes the replication-independent histone 3 variant H3.3, were observed in 31% of tumours, and led to amino acid substitutions at two critical positions within the histone tail (K27M, G34R/G34V) involved in key regulatory post-translational modifications. Mutations in ATRX (α-thalassaemia/mental retardation syndrome X-linked) and DAXX (death-domain associated protein), encoding two subunits of a chromatin remodelling complex required for H3.3 incorporation at pericentric heterochromatin and telomeres, were identified in 31% of samples overall, and in 100% of tumours harbouring a G34R or G34V H3.3 mutation. Somatic TP53 mutations were identified in 54% of all cases, and in 86% of samples with H3F3A and/or ATRX mutations. Screening of a large cohort of gliomas of various grades and histologies (n = 784) showed H3F3A mutations to be specific to GBM and highly prevalent in children and young adults. Furthermore, the presence of H3F3A/ATRX-DAXX/TP53 mutations was strongly associated with alternative lengthening of telomeres and specific gene expression profiles. This is, to our knowledge, the first report to highlight recurrent mutations in a regulatory histone in humans, and our data suggest that defects of the chromatin architecture underlie paediatric and young adult GBM pathogenesis.

Published
2012
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49. Acquired Omenn-like syndrome, a novel posttransplant autoaggression syndrome reversed by rapamycin.

Author

Vinh DC, Bin Dhuban K, Mason H, Lejtenyi D, Jung S, Sheppard DC, Faury D, Jabado N, and Piccirillo CA

Subjects
Female, Humans, Middle Aged, T-Lymphocyte Subsets immunology, Treatment Outcome, Graft vs Host Disease diagnosis, Graft vs Host Disease drug therapy, Hematopoietic Stem Cell Transplantation adverse effects, Immunologic Factors administration & dosage, Sirolimus administration & dosage
Abstract

Graft-versus-host disease is uncommon in autologous hematopoietic cell transplantation (HCT) and is typically brief and mild. We report unusual, protracted, and severe Omenn syndrome-like autoaggression following autologous HCT. We identified a profound FOXP3(+) regulatory T cell defect that coincided with hyperinflammatory T cell responses which were reversible with rapamycin in vitro.

Published
2012
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50. Genetic aberrations leading to MAPK pathway activation mediate oncogene-induced senescence in sporadic pilocytic astrocytomas.

Author

Jacob K, Quang-Khuong DA, Jones DT, Witt H, Lambert S, Albrecht S, Witt O, Vezina C, Shirinian M, Faury D, Garami M, Hauser P, Klekner A, Bognar L, Farmer JP, Montes JL, Atkinson J, Hawkins C, Korshunov A, Collins VP, Pfister SM, Tabori U, and Jabado N

Subjects
Adolescent, Astrocytoma pathology, Biomarkers, Tumor genetics, Biomarkers, Tumor metabolism, Brain Neoplasms pathology, Cell Line, Cellular Senescence genetics, Child, Child, Preschool, Cohort Studies, Cyclin-Dependent Kinase Inhibitor p16 genetics, Cyclin-Dependent Kinase Inhibitor p16 metabolism, Female, Gene Expression, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Infant, Male, Mitogen-Activated Protein Kinases metabolism, Oncogene Proteins genetics, Proto-Oncogene Proteins B-raf genetics, Proto-Oncogene Proteins B-raf metabolism, Astrocytoma genetics, Astrocytoma metabolism, Brain Neoplasms genetics, Brain Neoplasms metabolism, MAP Kinase Signaling System genetics, Oncogene Proteins metabolism
Abstract

Purpose: Oncogenic BRAF/Ras or NF1 loss can potentially trigger oncogene-induced senescence (OIS) through activation of the mitogen-activated protein kinase (MAPK) pathway. Somatic genetic abnormalities affecting this pathway occur in the majority of pilocytic astrocytomas (PA), the most prevalent brain neoplasm in children. We investigated whether OIS is induced in PA., Experimental Design: We tested expression of established senescence markers in three independent cohorts of sporadic PA. We also assessed for OIS in vitro, using forced expression of wild-type and V600E-mutant BRAF in two astrocytic cell lines: human telomerase reverse transcriptase (hTERT)-immortalized astrocytes and fetal astrocytes., Results: Our results indicate that PAs are senescent as evidenced by marked senescence-associated acidic β-galactosidase activity, low KI-67 index, and induction of p16(INK4a) but not p53 in the majority of 52 PA samples (46 of 52; 88.5%). Overexpression of a number of senescence-associated genes [CDKN2A (p16), CDKN1A (p21), CEBPB, GADD45A, and IGFBP7] was shown at the mRNA level in two independent PA tumor series. In vitro, sustained activation of wild-type or mutant BRAF induced OIS in both astrocytic cell lines. Loss of p16(INK4a) in immortalized astrocytes abrogated OIS, indicative of the role of this pathway in mediating this phenomenon in astrocytes. OIS is a mechanism of tumor suppression that restricts the progression of benign tumors. We show that it is triggered in PAs through p16(INK4a) pathway induction following aberrant MAPK activation., Conclusions: OIS may account for the slow growth pattern in PA, the lack of progression to higher-grade astrocytomas, and the high overall survival of affected patients.

Published
2011
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